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+Title: Large Language Models for Controllable Multi-property Multi-objective Molecule Optimization
+
+URL Source: https://arxiv.org/html/2505.23987
+
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+ Abstract
+1Introduction
+2
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+3
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ Models
+4Experimental Setup
+5Experimental Results
+6Conclusion
+7Limitations
+8Impact Statement
+9Ethics Statement
+ References
+
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+License: CC BY 4.0
+arXiv:2505.23987v1 [cs.LG] 29 May 2025
+Large Language Models for Controllable Multi-property Multi-objective Molecule Optimization
+Vishal Dey1, Xiao Hu1, Xia Ning1,2,3,4
+1 Department of Computer Science and Engineering, The Ohio State University, USA
+2 Translational Data Analytics Institute, The Ohio State University, USA
+3Department of Biomedical Informatics, The Ohio State University, USA
+4 College of Pharmacy, The Ohio State University, USA
+Correspondence: ning.104@osu.edu
+Abstract
+
+In real-world drug design, molecule optimization requires selectively improving multiple molecular properties up to pharmaceutically relevant levels, while maintaining others that already meet such criteria. However, existing computational approaches and instruction-tuned LLMs fail to capture such nuanced property-specific objectives, limiting their practical applicability. To address this, we introduce 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+, the first instruction-tuning dataset focused on multi-property optimization with explicit, property-specific objectives. Leveraging 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+, we develop 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s, a series of instruction-tuned LLMs that can perform targeted property-specific optimization. Our experiments across 5 in-distribution and 5 out-of-distribution tasks show that 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s consistently outperform strong baselines, achieving up to 126% higher success rate. Notably, 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s exhibit impressive 0-shot generalization to novel optimization tasks and unseen instructions. This offers a step toward a foundational LLM to support realistic, diverse optimizations with property-specific objectives. 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ and code are accessible through https://github.com/ninglab/GeLLMO-C.
+
+Large Language Models for Controllable Multi-property Multi-objective Molecule Optimization
+
+
+
+
+Vishal Dey1, Xiao Hu1, Xia Ning1,2,3,4
+1 Department of Computer Science and Engineering, The Ohio State University, USA
+2 Translational Data Analytics Institute, The Ohio State University, USA
+3Department of Biomedical Informatics, The Ohio State University, USA
+4 College of Pharmacy, The Ohio State University, USA
+Correspondence: ning.104@osu.edu
+
+
+
+1Introduction
+
+Developing a new drug is a time-consuming and expensive process, requiring over a decade and $2 billions Sertkaya et al. (2024). A key stage in this process is lead optimization Nicolaou and Brown (2013), where “hit" molecules – exhibiting promising early-stage bioactivity against drug targets – are optimized for multiple molecular properties Nicolotti et al. (2011) critical for pharmaceutical success. In practice, this stage often requires improving specific properties up to a pharmaceutically significant level, while maintaining already desirable ones within acceptable bounds. We refer to this setting as controllable multi-property, multi-objective optimization (C-MuMO), allowing for property-specific objectives, and thus greater control over the optimization.
+
+Such controllable optimization requires navigating complex trade-offs among multiple properties that are often competing or even conflicting Niu et al. (2024). For instance, optimizing an oral antipsychotic drug requires sufficiently high blood-brain barrier permeability (BBBP) Pollak et al. (2018) and dopamine receptor D2 (DRD2) inhibition Seeman (2001) to access the central nervous system (CNS) and block dopamine receptors in the CNS Seeman et al. (1976). Meanwhile, properties related to toxicity, such as Potassium (K+) channel inhibition must be lowered, since excessive inhibition of K+ channels in the brain Shepard et al. (2007) can cause fatal cardiac arrythmias Sanguinetti and Tristani-Firouzi (2006). Additionally, properties supporting oral bioavailability, such as intestinal absorption, must be maintained if they already meet desirable levels. These trade-offs highlight the need for property-specific objectives to mimic realistic optimization tasks.
+
+Most existing computational approaches Gao et al. (2022); Jensen (2019); You et al. (2018); Blaschke et al. (2020) cannot handle tasks with multiple objectives. Furthermore, existing approaches for multi-objective optimization Sun et al. (2022); Kim et al. (2024); Wu et al. (2024) rely on manually curated reward functions and careful task-specific tuning – limiting their scalability and applicability to diverse tasks in practice. We refer readers to Appendix A for a detailed review of existing approaches. Recently, instruction-tuned LLMs Dey et al. (2025), demonstrated strong performance on diverse multi-property optimization tasks. However, they only tackle tasks where all properties should be improved simultaneously. This setting fails to capture the nuanced property-specific objectives prevalent in realistic lead optimization.
+
+Figure 1:Overview of 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ and 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+
+To address these critical limitations, we introduce 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+, the first high-quality instruction-tuning dataset designed for C-MuMO tasks involving up to 10 molecular properties. Unlike prior datasets that require all properties to improve, 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ explicitly incorporates controllable property-specific objectives – specifying which properties must be improved up to a user-defined property-specific threshold, and which must be maintained within acceptable bounds. This design better reflects real-world lead optimization, where some properties reach pharmaceutically significant levels in early stages, while others require multiple iterations for further improvement.
+
+Built on 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+, we introduce a family of Generalizable Large Language Models for Multi-property, Multi-Objective Controllable optimization, 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+, by instruction-tuning general-purpose LLMs. 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ is trained to handle tasks requiring selective improvement of specific properties while maintaining already desirable ones. We develop both specialist and generalist variants. Each specialist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ is trained on a single property combination with multiple controllable multi-objective tasks. Generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ is trained across diverse multi-property combinations and multiple controllable objectives within each combination, enabling cross-task knowledge transfer. This enables a single foundational model to handle novel and diverse C-MuMO tasks without task-specific fine-tuning.
+
+We evaluate our 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ models with strong general-purpose LLMs and foundational LLMs for chemistry across 5 in-distribution (IND) and 5 out-of-distribution (OOD) tasks. Our results reveal several key findings: (1) All 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s substantially outperform state-of-the-art baselines on all IND and OOD tasks, with gains of up to 126% over the best baselines. (2) Generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s outperform specialist ones on 4 out of 5 IND tasks, with impressive gains of up to 26% on challenging tasks. (3) Generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s demonstrate remarkable 0-shot generalization to OOD tasks, outperforming strong baselines by 27% on average.
+
+To the best of our knowledge, 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ is the first large scale, high-quality instruction-tuning dataset specifically focused on controllable, multi-objective optimization with up to 10 properties. Generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s tuned on 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ demonstrate strong generalization abilities, which highlights their strong potential to tackle unseen, diverse C-MuMO tasks prevalent in realistic drug design scenarios. Figure 1 presents the overall framework of 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+. Dataset, models, and code are accessible through https://github.com/ninglab/GeLLMO-C.
+
+Table 1:Comparison among instruction-tuning datasets
+Comparison
+ 	
+𝙼𝚘𝚕𝙾𝚙𝚝
+⁢
+-
+⁢
+𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝𝚒𝚘𝚗𝚜
+	
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+	
+𝙲
+⁢
+-
+⁢
+����𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+
+Ye et al. (2025)	Dey et al. (2025)	(ours)
+
+Multi-objective
+ 	✗	✗	✓
+
+Threshold-based
+ 	✓	✗	✓
+
+Realistic
+ 	✗	✓	✓
+
+#properties
+ 	5	6	10
+
+#molecules
+ 	1,595,839	331,586	433,166
+
+#pairs
+ 	1,029,949	255,174	256,185
+
+#Total tasks
+ 	8	63	28,266
+
+  #Tasks 
+≥
+3
+ prop
+ 	0	42	27,401
+
+  #Eval 
+≥
+3
+ prop
+ 	0	10	119
+
+    #IND
+ 	8	5	51
+
+    #OOD
+ 	0	5	68
+2
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+
+In this paper, we introduce 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+, which provides control over each property objective in multi-property optimization tasks, unlike existing datasets such as 
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+. This enables models tuned on 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ to improve specific properties up to a user-defined level, while maintaining others at already desirable levels – a crucial capability that distinguishes 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ from existing datasets. These key differences are highlighted in Table 1.
+
+Problem Definition:
+
+A C-MuMO task is to modify a hit molecule 
+𝑀
+𝑥
+ into an improved lead molecule 
+𝑀
+𝑦
+, via structural modifications on 
+𝑀
+𝑥
+, guided by property-specific objectives – controlling which properties to be improved and the extent of such improvement. Given 
+𝒫
+ molecular properties, we define a pharmaceutically relevant level, 
+Θ
+𝑝
+, for each property 
+𝑝
+∈
+𝒫
+, Accordingly, 
+𝑝
+ is considered near-optimal if its score in 
+𝑀
+𝑥
+ – denoted as 
+𝑝
+⁢
+(
+𝑀
+𝑥
+)
+ – is more desirable than 
+Θ
+𝑝
+ (represented as 
+𝑝
+⁢
+(
+𝑀
+𝑥
+)
+≺
+Θ
+𝑝
+), and sub-optimal, otherwise (represented as 
+𝑝
+⁢
+(
+𝑀
+𝑥
+)
+⪰
+Θ
+𝑝
+). The desirability of each property is determined by the intended pharmaceutical goal, where either higher or lower property scores increase the molecule’s likelihood to be a successful drug candidate. For example, a higher BBBP is desired for drugs targeting the CNS to ensure their access to the brain, whereas a lower BBBP is desired for peripheral targets to prevent damage to the CNS.
+
+Formally, a C-MuMO task optimizing 
+𝑀
+𝑥
+ to 
+𝑀
+𝑦
+ aims to improve all sub-optimal properties 
+𝒫
+𝚒
+=
+{
+𝑝
+∈
+𝒫
+|
+𝑝
+⁢
+(
+𝑀
+𝑥
+)
+≺
+Θ
+𝑝
+}
+ while maintaining all near-optimal properties 
+𝒫
+𝚜
+=
+{
+𝑝
+∈
+𝒫
+∣
+𝑝
+⁢
+(
+𝑀
+𝑥
+)
+⪰
+Θ
+𝑝
+}
+ such that: (1) 
+𝑀
+𝑦
+ remains structurally similar to 
+𝑀
+𝑥
+ (similarity constraint); (2) 
+𝑀
+𝑦
+ improves upon 
+𝑀
+𝑥
+ in each sub-optimal property 
+𝑝
+∈
+𝒫
+𝚒
+ by at least a property-specific threshold, 
+Δ
+𝑝
+, represented as 
+(
+𝑀
+𝑥
+≺
+Δ
+𝑝
+𝑀
+𝑦
+)
+∀
+𝑝
+∈
+𝒫
+𝚒
+ (property improvement constraint); and (3) the absolute change from 
+𝑀
+𝑥
+ to 
+𝑀
+𝑦
+ in each near-optimal property 
+𝑝
+∈
+𝒫
+𝚜
+ remains within 
+Δ
+𝑝
+ to ensure such properties with already desirable scores are maintained, represented as 
+(
+𝑀
+𝑥
+≅
+Δ
+𝑝
+𝑀
+𝑦
+)
+∀
+𝑝
+∈
+𝒫
+𝚜
+ (property stability constraint).
+
+2.1Design Principles
+
+Following the above definition, we construct 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+, the first high-quality instruction tuning dataset for C-MuMO tasks with property-specific objectives. Our design of 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ is based on 5 key principles:
+
+(1) Real-world relevance:
+
+C-MuMO tasks are widely prevalent in real-world lead optimization, where some properties may already meet desirable levels while others require further improvement. Each optimization task in 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ is carefully curated to reflect nuanced multi-property objectives encountered in real-world drug design. By combining ADMET properties (e.g., intestinal absorption, mutagenicity) with properties related to specific therapeutic endpoints (e.g., dopamine receptor and potassium channel inhibition), 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ captures complex and realistic multi-property trade-offs.
+
+(2) Controllable multi-property threshold-based optimization:
+
+Unlike prior datasets such as 
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+, which enforces the same objective for all properties (i.e., ‘improve all’ simultaneously), 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ introduces property-specific objectives – specifying sub-optimal properties to improve and near-optimal ones to maintain – in addition to ‘improve all’ objectives. Such property-specific objectives enables modeling diverse multi-property trade-offs, thereby capturing more realistic optimization scenarios. Furthermore, 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ introduces property-specific thresholds, requiring each sub-optimal property to be improved up to a level considered sufficient for pharmaceutical success. This enables models tuned on 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ to learn more targeted optimization strategies and navigate nuanced multi-property trade-offs more effectively than models tuned on datasets lacking finer control. Meanwhile, learning such nuanced and controllable optimization introduces additional modeling challenges, making 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ a more practical and difficult dataset than existing ones.
+
+(3) Comprehensive coverage:
+
+Spanning across 10 pharmacologically relevant molecular properties, 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ covers a wide range of multi-property combinations, and multi-objective tasks with property-specific objectives for each property combination. This leads to a comprehensive set of optimization tasks, better capturing the complexity of real-world drug design.
+
+(4) Pairwise optimization:
+
+Following 
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+, 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ is constructed from molecule pairs that satisfy similarity, property improvement, and stability constraints. This enables models to effectively associate targeted structural modifications with property changes.
+
+(5) Diverse instructions:
+
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ provides diverse natural language instructions for each task with varied phrasings. This prevents instruction-tuned LLMs from overfitting to a specific phrasing, and enables them to generalize to unseen instructions – a crucial capability in practice, where task descriptions can widely vary.
+
+2.2Overview of 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ Tasks
+Table 2:Summary of 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ Tasks for Evaluation
+Type	
+𝒫
+-Comb	Properties	#Pairs	#Mols	#Test	#Tasks	Cat
+AMP↑ 	BBBP↑	CARC↓	DRD2↑	hERG↓	HIA↑	LIV↓	MUT↓	PlogP↑	QED↑					
+(
+Δ
+𝑝
+=
+)	0.1	0.1	0.2	0.1	0.2	0.1	0.1	0.1	1.0	0.1					
+(
+Θ
+𝑝
+=
+)	0.8	0.8	0.2	0.4	0.3	0.4	0.9	0.2	1.5	0.9					
+IND	
+𝙱𝙿𝚀
+	–	✓	–	–	–	–	–	–	✓	✓	700	1,371	500	7	
+𝙲𝚂
+
+
+𝙴𝙻𝚀
+	–	–	–	–	✓	–	✓	–	–	✓	700	1,376	500	7	
+𝙶𝚃
+
+
+𝙰𝙲𝙴𝙿
+	✓	–	✓	–	✓	–	–	–	✓	–	1,242	2,347	500	15	
+𝙶𝚃
+
+
+𝙱𝙳𝙿𝚀
+	–	✓	–	✓	–	–	–	–	✓	✓	895	1,561	500	13	
+𝙲𝚂
+
+
+𝙳𝙷𝙼𝚀
+	–	–	–	✓	–	✓	–	✓	–	✓	787	1,402	500	9	
+𝙲𝚂
+
+OOD	
+𝙲𝙳𝙴
+	–	–	✓	✓	✓	–	–	–	–	–	516	832	500	6	
+𝙲𝚂
+
+
+𝙰𝙱𝙼𝙿
+	✓	✓	–	–	–	–	–	✓	✓	–	1,500	2,809	500	15	
+𝙲𝚂
+
+
+𝙱𝙲𝙼𝚀
+	–	✓	✓	–	–	–	–	✓	–	✓	1,398	2,696	500	15	
+𝙲𝚂
+
+
+𝙱𝙳𝙴𝚀
+	–	✓	–	✓	✓	–	–	–	–	✓	603	840	500	11	
+𝙲𝚂
+
+
+𝙷𝙻𝙼𝙿𝚀
+	–	–	–	–	–	✓	✓	✓	✓	✓	1,800	3,329	500	21	
+𝙶𝚃
+• 
+
+“
+𝒫
+-Comb" denotes the combination of 
+𝒫
+ properties with multiple objectives. “#Pairs" and “#Mols", denote the number of molecule pairs and unique molecules in training, respectively. “#Test" and “#Tasks" denote the number of test samples and multi-property objectives for a specific property combination, respectively. “Cat" indicates task category. ✓indicates properties included in the task; – indicates properties not involved. ↑ and ↓ indicate whether higher or lower scores of a given property are desirable.
+
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ comprises a total of 28,266 tasks, with 27,401 tasks optimizing a combination of at least 3 properties. All tasks in 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ are systematically curated by combining subsets of 10 pharmacologically relevant molecular properties: (1) Penalized LogP (PlogP): representing solubility, lipophilicity, synthetic accessibility, and ring complexity – higher PlogP is typically preferred in drug candidates; (2) Quantitative Estimate of Drug-Likeness (QED): assessing overall drug-likeness by incorporating molecular weight, lipophilicity, and hydrogen bonding ability – higher QED is desired for better drug-likeness; (3) Parallel Artificial Membrane Permeability Assay (AMP): evaluating drug permeability across the cellular membrane – higher AMP indicates improved drug absorption; (4) Blood-Brain Barrier Permeability (BBBP): representing the ability of a drug to permeate the blood-brain barrier – higher BBBP is essential for CNS drugs; (5) human Intestinal Absorption (HIA): indicating the ability of a drug to be absorbed through the gastrointestinal tract – higher HIA supports effective absorption of orally administered drugs; (6) human Ether-à-go-go Related Gene inhibition (hERG): referring to the drug’s ability to inhibit the human ether-à-go-go related gene, which in turn blocks the potassium channel, causing severe cardiac issues – lower hERG is necessary to reduce cardiac risks; (7) Carcinogenicity (CARC): indicating the potential of a drug to induce cancer by damaging the genome or disrupting cellular processes – lower CARC is desired for safety; (8) Mutagenicity (MUT): referring to the likelihood of a drug causing genetic mutations – lower MUT scores are preferred to reduce genotoxicity; (9) Drug-induced Liver Injury (LIV): representing a drug’s potential to induce liver damage (hepatotoxicity) – lower DILI is crucial to reduce toxicity; (10) Dopamine Receptor D2 Inhibition (DRD2): indicating binding affinity to dopaminergic pathways – higher DRD2 scores are desired for antipsychotic drugs targeting the DRD2 receptor.
+
+We focus on these 10 properties due to their key role in determining a drug’s pharmacokinetic behavior, toxicity risk, and overall drug-likeness – essential factors in real-world lead optimization. Moreover, these properties are well-studied and typically considered in existing optimization benchmarks Gao et al. (2022); Dey et al. (2025). For evaluation, 10 representative property combinations (Section B) with 119 multi-objective tasks are selected and grouped into 51 IND and 68 OOD tasks. (Section 2.6). These tasks can be divided into 2 categories: (1) General Drug-Likeness and Toxicity (
+𝙶𝚃
+): tasks focused on broadly applicable molecular properties relevant for any successful drug candidate, irrespective of the specific therapeutic endpoint. (2) Context-Specific Objectives (
+𝙲𝚂
+): tasks involving properties that are specific to the therapeutic end-point, such as DRD2 inhibition or tissue-specific permeability (e.g., BBBP).
+
+2.3Constructing Task-Specific Training Pairs
+
+Following Algorithm 1, we construct task-specific training pairs 
+(
+𝑀
+𝑥
+,
+𝑀
+𝑦
+)
+ from the dataset curated by Chen et al. (2021), which contains 256K molecule pairs satisfying the similarity constraint (i.e., Tanimoto similarity > 0.6). Out of these pairs, we select those that satisfy all 
+𝒫
+𝚒
+ property improvement constraints (i.e., 
+(
+𝑀
+𝑥
+≺
+Δ
+𝑝
+𝑀
+𝑦
+)
+∀
+𝑝
+∈
+𝒫
+𝚒
+) and all 
+𝒫
+𝚜
+ property stability constraints (i.e., 
+(
+𝑀
+𝑥
+≅
+Δ
+𝑝
+𝑀
+𝑦
+)
+∀
+𝑝
+∈
+𝒫
+𝚜
+) for each task optimizing sub-optimal 
+𝒫
+𝚒
+ properties and near-optimal 
+𝒫
+𝚜
+ properties (Appendix B.1). For a given task with 
+𝒫
+ properties, each property 
+𝑝
+∈
+𝒫
+ is considered sub-optimal or near-optimal based on 
+Θ
+𝑝
+ (shown in Table 2) as described earlier in Section 2. These thresholds are set to the 60th percentile of all training molecules among 256K pairs, reflecting desirable scores for an optimized lead molecule.
+
+2.4Constructing Task-Specific Test Set
+
+We construct a test set by randomly sampling 250K molecules from ZINC Sterling and Irwin (2015), a widely used subset of commercially available molecules. All sampled molecules satisfy Lipsinki’s rule of 5 Lipinski et al. (2001), and do not overlap with the training set to ensure no data leakage. This creates an initial pool of drug-like molecules having some near-optimal properties with desirable scores, and some sub-optimal ones requiring further improvement. From this pool, we select a molecule 
+𝑀
+𝑥
+ into the test set of a task improving 
+𝒫
+𝚒
+ and maintaining 
+𝒫
+𝚜
+ properties, if 
+𝑀
+𝑥
+ has every property 
+𝑝
+∈
+𝒫
+𝚒
+ worse than 
+Θ
+𝑝
+, and every property 
+𝑝
+∈
+𝒫
+𝚜
+ exceeding 
+Θ
+𝑝
+. This selection ensures a representative test set for evaluation on diverse multi-objective tasks, given a specific property combination. Following this selection process, we randomly sample 500 molecules for each of 10 representative property combinations in evaluation.
+
+2.5Quality Control
+
+We implement several quality control measures, detailed in Appendix B.2, to ensure the integrity and rigor of 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+. We eliminate duplicate molecules by comparing their canonicalized SMILES representations. We compute all molecular property scores empirically using established and widely-used tools such as ADMET-AI Swanson et al. (2024). To promote robustness in instruction following, we curate 30 distinctly phrased instructions that convey the same optimization objective using varied semantics (Appendix C). To assess LLMs’ ability to generalize beyond seen instructions, we hold out one instruction per task during training and use it only during inference.
+
+2.6IND and OOD Tasks
+
+To rigorously evaluate instruction-tuned LLMs on both familiar and novel optimization scenarios, we split the 10 evaluation tasks into 2 groups:
+
+In-Distribution (IND) Tasks:
+
+IND tasks are defined by property combinations that appear in the training set. Performance on these tasks assess how effectively the model can apply its learned modification strategies to the exact property combinations and objectives it was specifically trained on.
+
+Out-of-Distribution (OOD) Tasks:
+
+OOD tasks involve novel multi-property combinations and novel multi-property objectives for each combination that are not used during training (i.e., unseen C-MuMO tasks). Note that although OOD property combinations are not used in training, each individual property is still used as part of other combinations in the training tasks. Success in OOD tasks demonstrates the model’s ability to transfer its knowledge to novel property combinations and novel multi-objective tasks for each unseen property combination without task-specific fine-tuning. This ability is crucial in practice, where emerging therapeutic goals often necessitate adapting to previously unseen multi-property trade-offs.
+
+3
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ Models
+
+We introduce 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s, a series of general-purpose LLMs instruction-tuned over 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+. 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ is tuned to follow property-specific objectives in 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+. Instruction tuning over molecule pairs enables 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ to implicitly encode how precise structural modifications map to multiple property changes Hansch (1969). 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ learns to apply such targeted modifications to improve sub-optimal properties beyond user-defined thresholds specified in the task instruction. 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ also learns to preserve specified near-optimal properties by avoiding structural modifications that would otherwise lower their scores. Learning such precise modifications strategies allows for explicit control over each property with varying objectives.
+
+We develop both specialist and generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s. Each specialist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+, denoted as 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙽
+, is fine-tuned on a single property combination of 
+𝑁
+ properties, with multiple objectives in that specific combination. This enables them to learn focused modification strategies specific to observed trade-offs for that property combination. In contrast, generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s are trained across multiple property combinations and multiple objectives in each combination. This promotes knowledge transfer of shared chemical semantics and modification strategies to tackle diverse property trade-offs with property-specific objectives. This enables generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ to act as a foundational LLM capable of handling novel tasks without task-specific retraining, while offering control over unseen multi-property objectives.
+
+Concretely, we develop a series of generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s, denoted as 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝙽
+)
+, each is jointly trained on multiple C-MuMO tasks involving diverse multi-property, multi-objective combinations with up to 
+𝑁
+ properties. To train these models, we fine-tune 2 general-purpose LLMs: Mistral-7B-Instruct-v0.3 AI (2023) and Llama3.1-8B-Instruct Grattafiori et al. (2024) by applying LoRA Hu et al. (2022) on every projection layer and the language modeling head. We perform 0-shot evaluations (i.e., without in-context examples) for all 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s. For each input molecule, we generate 20 candidates via beam search decoding. Additional details are provided in Appendix D.1.
+
+4Experimental Setup
+4.1Baselines
+
+We compare 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s against 2 categories of baseline models: (1) general-purpose LLMs: Mistral-7B Instruct-v0.3 AI (2023), Llama-3.1 8B-Instruct Touvron et al. (2023), Claude-3.5 and GPT-4o; and (2) foundational LLMs for chemistry: a Mistral-7B fine-tuned on diverse molecular tasks Yu et al. (2024), denoted as 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+. Existing non-LLM models require substantial effort on task-specific tuning or handcrafted reward functions, making them ill-suited baselines given the scale and diversity of 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+. We use few-shot prompting with only 1 in-context example for all general-purpose LLMs to balance generation quality with computational resources and expenses. For baselines that support beam-search decoding, we generate 20 candidate molecules per input using the same generation strategy as in 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+. Additional details and prompts are in Appendix D.2 and Appendix E, respectively.
+
+Table 3:Overall Performance in IND Tasks
+Model	
+𝙱𝙿𝚀
+		
+𝙴𝙻𝚀
+		
+𝙰𝙲𝙴𝙿
+		
+𝙱𝙳𝙿𝚀
+		
+𝙳𝙷𝙼𝚀
+
+
+𝚂𝚁
+↑ 	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑
+General-purpose LLMs
+Mistral (0-shot)	28.80	0.75	1.24		21.60	0.72	0.16		26.20	0.75	1.10		2.40	0.72	0.49		4.80	0.71	0.76
+Llama (0-shot)	33.60	0.70	0.78		16.60	0.74	0.10		17.20	0.74	0.69		8.80	0.72	1.67		6.00	0.73	1.35
+Claude-3.5 (0-shot)	51.80	0.68	0.89		20.00	0.64	0.20		29.60	0.71	0.69		11.20	0.67	1.80		5.20	0.63	1.84
+GPT-4o (0-shot)	30.20	0.72	0.55		16.60	0.72	0.10		22.20	0.74	0.52		4.20	0.72	3.98		5.80	0.72	0.88
+Mistral (1-shot)	72.80	0.63	1.26		74.80	0.59	0.28		63.80	0.64	1.03		21.60	0.59	4.76		25.60	0.55	1.89
+Llama (1-shot)	49.60	0.68	0.95		36.80	0.68	0.15		40.20	0.70	1.12		14.40	0.63	2.65		13.80	0.56	3.39
+Claude-3.5 (1-shot)	61.80	0.65	1.31		29.20	0.63	0.21		32.60	0.71	1.24		15.60	0.58	3.99		8.40	0.65	1.38
+GPT-4o (1-shot)	28.60	0.74	0.77		19.60	0.72	0.12		23.00	0.76	1.09		5.60	0.68	3.47		5.60	0.71	1.22
+Foundational LLMs for Chemistry
+LlaSMol-M	78.20	0.64	0.92		81.40	0.62	0.28		68.60	0.66	1.00		22.60	0.68	2.22		24.80	0.62	1.44
+Specialist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙽
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	71.00	0.57	2.59		81.80	0.55	0.39		85.60	0.54	2.46		56.60	0.50	5.48		44.60	0.57	2.96
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙽
+𝙻𝚕𝚊𝚖𝚊
+	84.20	0.58	2.09		85.40	0.53	0.41		88.00	0.54	2.24		43.60	0.58	4.85		35.40	0.65	2.63
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝚂𝚙𝚎𝚌
+ (%)	7.7	-9.4	127.2		4.9	-14.5	46.4		28.3	-18.2	124.0		150.4	-26.5	146.8		74.2	3.6	56.6
+Generalist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝙽
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	84.80	0.63	2.64		83.20	0.63	0.33		86.60	0.60	2.34		50.60	0.58	4.93		53.40	0.59	3.26
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝙽
+)
+𝙻𝚕𝚊𝚖𝚊
+	88.80	0.62	2.16		90.80	0.63	0.34		92.80	0.58	2.22		51.00	0.58	5.40		50.40	0.59	3.28
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	89.40	0.62	2.30		88.40	0.59	0.41		74.60	0.61	1.92		48.40	0.58	5.05		52.20	0.61	2.24
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+	79.40	0.57	2.67		79.00	0.56	0.41		72.60	0.57	2.27		42.60	0.55	5.89		41.80	0.57	3.32
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+ (%)	14.3	-3.1	150.0		11.5	1.6	21.4		35.3	-12.1	122.0		125.7	-14.7	143.2		108.6	7.3	72.5
+• 
+
+↑ and ↓ indicate whether a higher or lower metric is preferred, respectively. For each task, the best-performing model is in bold, and the best baseline is underlined. 
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝚂𝚙𝚎𝚌
+ and 
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+ represent the percentage improvement from the best specialist LLM and best generalist LLM over the best baseline, respectively. The best model in each group is selected based on 
+𝚂𝚁
+ for each task.
+
+4.2Evaluation Metrics
+
+We employ multiple evaluation metrics (detailed in Appendix D.3) to enable a comprehensive assessment. For clarity and brevity, we report results primarily using the following metrics: (1) Success Rate (
+𝚂𝚁
+): the proportion of input molecules successfully optimized, such that all sub-optimal properties are improved, and all near-optimal ones are maintained within their corresponding 
+Δ
+𝑝
+ – reflecting the model’s ability to follow property-specific objectives; (2) Similarity with input (
+𝚂𝚒𝚖
+): the average Tanimoto similarity Bajusz et al. (2015) between the optimized and corresponding input molecule; (3) Relative Improvement (
+𝚁𝙸
+): the relative improvement averaged across all sub-optimal properties. Higher 
+𝚂𝚁
+, 
+𝚂𝚒𝚖
+, and 
+𝚁𝙸
+ are preferred, denoting more successful and effective optimizations. In Appendix G, we report results with a stricter notion of success, via 
+𝚂𝚁
+𝛩
+, measuring success only if each property in the task exceeds 
+Θ
+𝑝
+.
+
+5Experimental Results
+Main Findings:
+
+The key findings are summarized as: (1) Both specialist and generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s consistently surpass general-purpose LLMs and foundational LLMs for chemistry across all IND (Section 5.1) and OOD tasks (Section 5.2), achieving up to 126% higher 
+𝚂𝚁
+ and 143% higher 
+𝚁𝙸
+. (2) Generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s outperform specialist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s on 4 out of 5 IND combinations, with 26% more successful optimizations on challenging tasks, such as 
+𝙳𝙷𝙼𝚀
+ (Section 5.1). (3) Generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s demonstrate remarkable 0-shot generalization to OOD tasks, surpassing the best general-purpose LLMs by 35% in 
+𝚂𝚁
+ and 76% in 
+𝚁𝙸
+ (Section 5.2). (4) Generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s exhibit strong generalization when prompted with unseen instructions across all IND tasks (Section 5.3).
+
+5.1IND Tasks
+
+Table 3 presents the performance comparison of 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s and baselines across all IND tasks. Detailed task-specific results are in Appendix G.1.
+
+Overall Comparison:
+
+Across all IND tasks, all specialist and generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s consistently outperform all baselines. Notably, the generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ outperforms the best baseline by 37% and 102% in 
+𝚂𝚁
+ and 
+𝚁𝙸
+ on average, indicating its superior ability as a foundational model to perform targeted modification across diverse C-MuMO tasks. On two challenging tasks, 
+𝙱𝙳𝙿𝚀
+ and 
+𝙳𝙷𝙼𝚀
+, with a specific therapeutic endpoint (DRD2 inhibition), both specialist and generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s successfully optimize as much as 150% and 126% more input molecules than the baselines, with even 1-fold better 
+𝚁𝙸
+. Such strong performance demonstrates the ability of 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s to tackle complex property trade-offs.
+
+Furthermore, when evaluated under the stricter success criteria (via 
+𝚂𝚁
+𝛩
+) – which requires each property to exceed pharmaceutically relevant thresholds (i.e., 
+Θ
+𝑝
+) – the performance gap between 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s and baselines becomes even more pronounced. Table A2 demonstrates that generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s outperform the best baseline by as much as 218% in 
+𝚂𝚁
+ and 313% in 
+𝚁𝙸
+. This highlights the ability of 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s to not only optimize more molecules, but also to improve each desired property up to significant levels.
+
+Comparison between specialist and generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+:
+
+Table 3 demonstrates that generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s outperform specialist ones on 4 out of 5 IND combinations, with particularly large gains on the challenging 
+𝙳𝙷𝙼𝚀
+ tasks. This trend is prominent in tasks with fewer task-specific training pairs, such as 
+𝙱𝙿𝚀
+, 
+𝙴𝙻𝚀
+, and 
+𝙳𝙷𝙼𝚀
+, where generalist models outperform specialist ones by up to 26% in 
+𝚂𝚁
+. Limited training pairs in these tasks hinder the specialist models to learn robust modification strategies. In contrast, generalist ones benefit from transferable knowledge of property trade-offs and learn optimization strategies from other diverse multi-property, multi-objective training tasks.
+
+Interestingly, in the 
+𝙱𝙳𝙿𝚀
+ tasks, despite having only 895 pairs, 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙽
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ outperforms all generalist ones. The generalist variant, 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝙽
+)
+, – trained only on tasks involving BBBP, DRD2, PlogP and QED – remains competitive due to its focused training on these specific properties. In contrast, 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+ – trained on all possible property combinations involving up to 10 properties – performs worse than 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝙽
+)
+ and specialist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+. This could be due to 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+ encountering tasks with competing or conflicting objectives, which weakens its ability to specialize in 
+𝙱𝙳𝙿𝚀
+-specific trade-offs. This highlights a key challenge in developing foundational models: while multi-task tuning promotes cross-task knowledge transfer, it may also introduce conflicts that negatively impact performance on specialized tasks (e.g., 
+𝙱𝙳𝙿𝚀
+).
+
+Table 4:Overall Performance in OOD Tasks
+Model	
+𝙲𝙳𝙴
+		
+𝙰𝙱𝙼𝙿
+		
+𝙱𝙲𝙼𝚀
+		
+���𝙳𝙴𝚀
+		
+𝙷𝙻𝙼𝙿𝚀
+
+
+𝚂𝚁
+↑ 	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑
+General-purpose LLMs
+Mistral (0-shot)	3.00	0.73	1.33		23.00	0.77	0.93		25.40	0.69	0.25		3.00	0.71	1.05		11.60	0.79	1.76
+Llama (0-shot)	6.80	0.68	0.77		44.60	0.71	0.61		20.40	0.72	0.20		2.20	0.68	0.60		20.20	0.72	0.68
+Claude-3.5 (0-shot)	6.80	0.70	1.07		43.60	0.70	0.80		30.00	0.64	0.26		4.80	0.62	0.57		21.00	0.66	0.59
+GPT-4o (0-shot)	3.80	0.74	1.56		27.00	0.73	0.51		19.60	0.72	0.19		3.40	0.71	0.42		12.80	0.72	0.47
+Mistral (1-shot)	30.60	0.62	1.66		73.20	0.64	1.09		63.80	0.60	0.31		21.60	0.58	1.16		55.60	0.62	0.77
+Llama (1-shot)	18.20	0.55	1.51		60.80	0.70	0.83		41.60	0.67	0.23		11.40	0.51	1.54		28.00	0.70	0.75
+Claude-3.5 (1-shot)	8.40	0.66	1.09		45.20	0.64	0.87		32.40	0.61	0.30		7.20	0.55	1.22		25.00	0.61	0.72
+GPT-4o (1-shot)	7.00	0.72	1.04		34.40	0.74	0.65		23.40	0.73	0.21		2.20	0.70	0.83		13.40	0.71	0.65
+Foundational LLMs for Chemistry
+
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	29.80	0.61	1.28		72.40	0.67	0.78		72.80	0.63	0.30		18.20	0.60	0.65		37.80	0.68	0.66
+Generalist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	39.80	0.58	1.66		86.60	0.63	1.68		84.20	0.62	0.42		29.20	0.60	1.22		74.60	0.61	1.36
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+	33.20	0.55	1.50		79.60	0.58	1.81		80.00	0.57	0.44		28.40	0.58	0.88		65.40	0.58	1.35
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+ (%)	30.1	-6.5	0.0		18.3	-1.6	54.1		15.7	-1.6	40.0		35.2	3.4	5.2		34.2	-1.6	76.6
+• 
+
+The metrics, notations and formatting have the same meanings as those in Table 3.
+
+Comparison with general-purpose LLMs:
+
+Table 3 shows that all 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s consistently outperform all general-purpose LLMs across all IND tasks, achieving up to 109% higher 
+𝚂𝚁
+ than the best general-purpose LLM, Mistral (1-shot). This strong performance gap underscores the benefit of instruction tuning on molecule pairs, which enables 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s to learn robust and effective modification strategies that are difficult for general-purpose LLMs to learn through in-context examples alone. Moreover, general-purpose LLMs exhibit lower 
+𝚁𝙸
+ among the limited successfully optimized molecules, compared to 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s. This demonstrates the ability of 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s to perform more targeted modifications to yield substantial improvements on each sub-optimal property.
+
+Comparison with foundational LLMs for chemistry:
+
+All 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s substantially outperform the SoTA foundational LLM for chemistry, 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+, on all IND tasks. Another foundational LLM, 
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+, performs worse than 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+ (Appendix G). Notably, on 
+𝙱𝙳𝙿𝚀
+ and 
+𝙳𝙷𝙼𝚀
+, 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ achieves a 126% and 115% higher 
+𝚂𝚁
+, respectively, with higher 
+𝚁𝙸
+ by 143% and 126%, respectively, compared to 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+. While 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+ is instruction-tuned on a broad range of molecular tasks, 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s are specifically instruction-tuned on different multi-property optimization tasks. This highlights the efficacy of instruction-tuning on optimization tasks to learn targeted modifications and navigate multi-property trade-offs. Appendix F presents 2 cases of such targeted modifications.
+
+5.2OOD Tasks
+
+Table 4 presents the performance of 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s and baselines across all OOD tasks. Since 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙽
+s and 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝙽
+)
+ models use task-specific pairs, they are inapplicable to OOD tasks. Overall, generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s exhibit strong 0-shot generalization to novel C-MuMO tasks, consistently outperforming all baselines. Specifically, the best-performing generalist model, 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+, achieves an average 
+𝚂𝚁
+ of 63% across all tasks, outperforming the best baseline, Mistral (1-shot), by as much as 35% and 77% in 
+𝚂��
+ and 
+𝚁𝙸
+, respectively. These strong results demonstrate the remarkable ability of generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s to learn transferable optimization strategies and tackle unseen controllable property-specific objectives during inference. Such generalizability is crucial in practice, where evolving therapeutic goals often introduce novel property combinations and novel objectives.
+
+5.3Generalizability to Unseen Instructions
+
+Table A13 compares specialist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s with generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s when evaluated with a hold-out instruction and property name (Appendix C). Overall, specialist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s exhibit a performance drop of over 5% in 
+𝚂𝚁
+ on 2 out of 5 IND combinations. In contrast, generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s retain consistent performance on all tasks. This indicates that generalist models – trained on more tasks and instructions – can generalize better to unseen instructions with different phrasings. Such generalizability is crucial in practice, where task instructions can vary widely. Notably, 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+ demonstrates more robustness than 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+, reflecting a reduced tendency to overfit to specific wordings.
+
+6Conclusion
+
+In this paper, we introduced 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+, the first instruction-tuning dataset enabling controllable molecule optimization with property-specific objectives. Leveraging 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+, we developed 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s, that consistently and largely outperform strong general-purpose LLMs and foundational LLMs for chemistry across all IND and OOD tasks. Moreover, generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s exhibit strong generalization to unseen tasks, outperforming baselines by 27% on average. This indicates the potential of 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ as a foundational model to tackle diverse tasks with realistic, controllable objectives reflecting real-world scenarios.
+
+7Limitations
+
+While our work represents a significant step toward controllable, multi-objective molecule optimization, several limitations remain: (1) Our current framework is designed for single-step optimization. In practice, optimizing molecules to reach pharmaceutically meaningful thresholds for all properties may require multiple iterative modifications. Designing a feedback mechanism for 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ or intermediate reward signal to guide iterative refinement is non-trivial and is a direction for future work. (2) We rely on computational predictors for molecular properties. Although they are well-established and widely used, they may introduce inaccuracies and may not always reflect exact experimental outcomes. Incorporating experimentally validated datasets or feedback to LLMs with wet-lab data is a promising direction for future work. (3) Although we demonstrate strong generalization to unseen instructions, our instruction templates are still synthetically generated. Future work could explore more diverse linguistic variation to test LLM robustness in truly open-ended settings.
+
+8Impact Statement
+
+This work presents the first instruction-tuning dataset, 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+, that explicitly supports property-specific objectives in multi-property molecule optimization – enabling models to selectively improve sub-optimal properties while preserving near-optimal ones. Built on this dataset, our developed instruction-tuned LLMs (
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+) represent a substantial advancement toward controllable molecule optimization, addressing practical drug design requirements often overlooked by existing approaches. 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s consistently outperform both strong general-purpose LLMs and foundational LLMs for chemistry across challenging optimization tasks involving conflicting objectives. By demonstrating robust generalization to novel property combinations and novel multi-property constraints, 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ paves the way for scalable, general-purpose foundation LLMs that can flexibly handle diverse drug design constraints. We anticipate that 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+ will serve as a building block for future iterative LLM optimization frameworks.
+
+Broader Impacts:
+
+The development of foundational LLMs for controllable multi-property molecule optimization represents a significant step toward AI-based molecular design tools. Their ability to follow property-specific instructions enables iterative optimization workflows, where molecules are refined over multiple steps based on intermediate feedback – a common and necessary paradigm in real-world lead optimization. Through natural language instructions, these models can be flexibly adapted to a variety of drug design scenarios without extensive retraining. Such flexibility lowers the barrier to deploying intelligent drug design pipelines, especially for researchers with limited computational or domain resources. Ultimately, such scalable and generalizable frameworks have the potential to accelerate early-stage drug development, reduce experimental burden, and democratize access to advanced drug design capabilities.
+
+9Ethics Statement
+
+Our work introduces instruction-tuning dataset, 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ and 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s tuned on 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ for multi-property molecule optimization. While 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ is curated with drug-like molecule and to improve pharmaceutically relevant and desirable properties, we cannot fully guarantee the absence of harmful compounds or the potential for misuse. Notably, 4 of the 10 properties in 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ – carcinogenicity, hERG inhibition, drug-induced liver injury, and mutagenicity – are directly related to drug toxicity. Our models are explicitly tuned to minimize these property scores, and thus, to improve drug safety profiles aligned with widely accepted pharmacological desirability. The objective is to generate drug-like molecules with reduced toxicity, not to increase toxicity or discover harmful compounds.
+
+Given that our models are fine-tuned on general-purpose open-source LLMs, they may still retain knowledge about toxic substructures or chemicals from the broader pretraining corpus. While our instruction-tuning encourages models to generate molecules with more pharmaceutically desirable profiles, we cannot fully eliminate the possibility of generating undesirable molecules if misused or prompted adversarially.
+
+We strongly discourage any application of 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s outside responsible drug discovery research. Deployment of these models should be accompanied by toxicity screening, expert review, and strong usage controls. We expect all users of our dataset and models to uphold the highest standards of ethical research and to take appropriate precautions to prevent unintended consequences.
+
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+↑
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+Appendix ARelated Work
+
+Computational approaches have primarily focused on single- or double-property optimization tasks You et al. (2018); Blaschke et al. (2020); Xie et al. (2021); Bung et al. (2022); Sun et al. (2022). Graph-based methods such as Modof Chen et al. (2021), MIMOSA Fu et al. (2021), and f-RAG Lee et al. (2024) perform substructure modifications on molecular graphs, while sequence-based methods like Chemformer Irwin et al. (2022) and Prompt-MolOpt Wu et al. (2024), formulate optimization as translation tasks over SMILES strings. Genetic algorithm-based methods, GraphGA Jensen (2019) and MolLeo Wang et al. (2025) can optimize multiple properties but generate entirely new molecular scaffolds, limiting their practical utility. Furthermore, existing methods Jensen (2019); Wang et al. (2025); Kim et al. (2024); Yang et al. (2021), require task-specific fine-tuning and expert-curated reward functions to model multi-property trade-offs, limiting their scalability and applicability.
+
+Recently, LLMs have demonstrated great promise for molecule optimization through natural language instructions Chang et al. (2024). ChatDrug Liu et al. (2024) and Re3DF Le and Chawla (2024) adopt multi-turn dialogue frameworks for iterative optimization. However, their reliance on closed-source APIs leads to high costs. DrugAssist Ye et al. (2025) developed task-specific instruction-tuned LLMs limited to optimization tasks with up to 2 properties.  Dey et al. (2025) introduced 
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ – a large-scale instruction-tuning dataset specifically focused on multi-property optimization tasks involving 3 or more properties – and further demonstrated the remarkable generalization abilities of instruction-tuned LLMs. However, 
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ does not provide controllable property-specific objectives required to mimic realistic C-MuMO tasks.
+
+Appendix BDetails on 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+B.1Details on Task Construction
+Input: Molecule pair 
+(
+𝑀
+𝑥
+,
+𝑀
+𝑦
+)
+, Pharmaceutically-relevant levels 
+{
+Θ
+𝑝
+}
+, Improvement thresholds 
+{
+Δ
+𝑝
+}
+, Set of properties 
+𝒫
+Output: List of valid C-MuMO tasks 
+𝒯
+ for 
+(
+𝑀
+𝑥
+,
+𝑀
+𝑦
+)
+ with at most 
+𝒫
+ properties
+Initialize 
+𝒯
+←
+∅
+ ;
+foreach 
+𝑝
+∈
+𝒫
+ do
+       Compute 
+change
+⁢
+[
+𝑝
+]
+←
+𝑝
+⁢
+(
+𝑀
+𝑦
+)
+−
+𝑝
+⁢
+(
+𝑀
+𝑥
+)
+ ;
+       Set 
+dir
+⁢
+[
+𝑝
+]
+←
+ (
+change
+⁢
+[
+𝑝
+]
+>
+0
+) if higher 
+𝑝
+ is desirable, else negative ;
+      
+// Identify Sub-optimal and near-optimal Properties:
+𝒫
+𝚒
+ 
+←
+{
+𝑝
+∈
+𝒫
+𝚒
+∣
+abs(change)
+⁢
+[
+𝑝
+]
+>
+Δ
+𝑝
+}
+ ;
+𝒫
+𝚜
+ 
+←
+{
+𝑝
+∈
+𝒫
+𝚜
+∣
+abs(change)
+[
+𝑝
+]
+≤
+Δ
+𝑝
+ and 
+𝑝
+(
+𝑀
+𝑥
+)
+⪰
+Θ
+𝑝
+}
+ ;
+foreach property subset 
+𝒞
+⊆
+𝒫
+ with 
+|
+𝒞
+|
+≥
+1
+ do
+       
+𝒞
+𝑖
+←
+𝐶
+∩
+𝒫
+𝚒
+ // Identify sub-optimal subset ;
+      
+      if 
+𝒞
+𝑖
+=
+∅
+ then
+            continue // Skip if no sub-optimal properties
+      
+      if not all 
+dir
+⁢
+[
+𝑝
+]
+ in 
+𝒞
+𝑖
+ are the same then
+             continue // Require improvement in all sub-optimal ones
+      
+      NeedSwap 
+←
+ true if all 
+dir
+⁢
+[
+𝑝
+]
+ in 
+𝒞
+𝑖
+ are opposite of desired // Determine swap condition ;
+      
+      if NeedSwap then
+            Swap 
+𝑀
+𝑥
+↔
+𝑀
+𝑦
+ // Ensure correct direction of improvement ;
+            
+      
+      
+𝒞
+𝑠
+←
+𝐶
+∩
+𝒫
+𝚜
+ // Identify near-optimal subset ;
+      
+      Construct task 
+𝑡
+=
+(
+𝑀
+𝑥
+,
+𝑀
+𝑦
+,
+𝒞
+𝑖
+,
+𝒞
+𝑠
+)
+ // An optimization task ;
+      
+      
+𝒯
+←
+𝒯
+∪
+{
+𝑡
+}
+return 
+𝒯
+Algorithm 1 C-MuMO Task Construction from a Molecule Pair
+
+Algorithm 1 presents a pseudocode for constructing all valid C-MuMO tasks with all possible property combinations involving up to 
+𝒫
+ properties, given a molecule pair 
+(
+𝑀
+𝑥
+,
+𝑀
+𝑦
+)
+. To construct 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+, we run Algorithm 1 on a random sample of 100K molecule pairs sourced from Chen et al. (2021). To create training pairs for a given combination with 
+𝑁
+ properties, we select only those tasks out of all C-MuMO tasks that have all 
+𝑁
+ properties involved. For example, to create task-specific training pairs for 
+𝙱𝙳𝙿𝚀
+, we select only tasks that involve all 4 properties: 
+𝒯
+BDPQ
+=
+{
+𝑡
+=
+(
+𝑀
+𝑥
+,
+𝑀
+𝑦
+,
+𝒞
+𝑖
+,
+𝒞
+𝑠
+)
+∈
+𝒯
+∣
+(
+𝒞
+𝑖
+∪
+𝒞
+𝑠
+)
+=
+𝒫
+}
+ where 
+𝒫
+=
+{
+BBBP, DRD2, PlogP and QED
+}
+.
+
+We use at most 100 molecule pairs for each C-MuMO task (i.e., a unique property combination with explicit property-specific objectives) to balance efficiency and task diversity. Given that 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ contains over 28K such tasks, training a generalist model with all possible pairs would be computationally prohibitive and may overemphasize overrepresented tasks. Limiting the number of examples per task ensures that the instruction-tuned model is exposed to a broad spectrum of multi-property trade-offs without biasing toward specific tasks. This design supports better generalization across diverse optimization objectives while keeping training tractable.
+
+B.2Details on Quality Control
+
+To ensure a high-quality instruction-tuning dataset, we applied a series of quality control procedures.
+
+Molecule Deduplication and Canonicalization:
+
+All molecules in 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ are represented using canonical SMILES strings Weininger (1988), standardized via RDKit rdk (2025). We remove molecules with identical canonicalized SMILES that are structurally equivalent, thereby eliminating redundancy and ensuring that each molecule appears only once.
+
+Empirical Property Computation:
+
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ uses computationally predicted scores to annotate each molecule with 10 pharmacologically relevant molecular properties. These scores are computed using well-established, high-performing tools widely used in the molecular machine learning community. Specifically, we adopt the official implementation from You et al. (2018) for computing DRD2 and PlogP scores, and leverage the ADMET-AI tool Swanson et al. (2024) to compute all other properties. These tools rank among the top-performing predictors in the Therapeutics Data Commons (TDC) benchmark Catacutan et al. (2024), and have been extensively validated and adopted in recent studies Wei et al. (2024); Thomas et al. (2024); Wahnou et al. (2024); Dey et al. (2025); Averly et al. (2025). They provide a reliable, computationally efficient means to estimate property scores at scale, enabling the construction of high-quality datasets with broad coverage of chemical space.
+
+While these predictors are not experimentally validated, they demonstrate strong alignment with experimentally measured values and are widely accepted as practical surrogates in virtual screening pipelines. Notably, experimentally validated measurements are severely limited for many key pharmacological properties. For instance, public datasets contain fewer than 2,000 experimentally measured BBBP values – orders of magnitude below what is needed to train large-scale deep learning models or instruction-tuned LLMs. Given these constraints, the use of empirical predictors is not only standard but necessary for enabling scalable dataset creation and evaluation.
+
+Instruction Diversity and Generation:
+
+To avoid LLM overfitting to specific phrasings and to promote generalization to natural word variations in task formulation, we ensure that each optimization task is associated with a diverse set of instructions. Starting from a manually written seed prompt, we use GPT-4o OpenAI (2024) to generate several paraphrased variants that preserve the semantic intent while differing in structure and wording. From these, we select 30 semantically equivalent but syntactically diverse instructions per task to include in the training data.
+
+To explicitly assess the models’ ability to generalize to new instructions, we hold out one instruction per task as unseen during instruction-tuning. This unseen instruction is then used during evaluation to measure robustness to novel phrasings. This design allows us to evaluate not only task-level generalization but also linguistic flexibility in following diverse natural language instructions. All instructions used in training and testing are provided in Appendix C.
+
+B.3Details on IND Tasks
+1. 
+
+𝙱𝙿𝚀
+ (BBBP, PlogP, QED): This task involves 7 diverse combinations of property-specific objectives across BBBP, PlogP, and QED – three properties central to CNS drug design. Each optimization task may involve improving one or more of these properties while maintaining or improving the others. Optimizing 7 diverse multi-objective combinations of BBBP, PlogP, and QED simulates early-stage filtering of CNS-active hits.
+
+2. 
+
+𝙴𝙻𝚀
+ (hERG, LIV, QED): Here, the focus is on toxicity-related properties and overall drug-likeness. hERG inhibition and liver toxicity are two major causes of clinical trial failures, while QED ensures retained drug-like features. A good optimizer must reduce toxicity signals while preserving beneficial characteristics, reflecting real-world needs in late-stage lead optimization, where safety issues are addressed without sacrificing potency.
+
+3. 
+
+𝙰𝙲𝙴𝙿
+ (AMP, CARC, hERG, PlogP): This task consists of 15 optimization combinations focused on absorption and toxicity-related properties. Each task may require improving any subset of AMP (permeability), CARC (carcinogenicity), hERG (cardiotoxicity), or PlogP (lipophilicity), while stabilizing the rest. It captures the complex trade-offs typical in preclinical candidate refinement, where ADME and safety must be simultaneously addressed.
+
+4. 
+
+𝙱𝙳𝙿𝚀
+ (BBBP, DRD2, PlogP, QED): This combination includes 13 challenging optimization tasks for antipsychotic drug design. These require optimization for BBB penetration and DRD2 activity – two critical endpoints for efficacy – while maintaining lipophilicity and drug-likeness. It embodies a highly targeted CNS design task and is one of the most challenging due to strong interdependencies among all properties.
+
+5. 
+
+𝙳𝙷𝙼𝚀
+ (DRD2, HIA, MUT, QED): This combination involves optimization of 9 different multi-objective tasks to optimize a CNS drug target that must bind to DRD2 receptors while exhibiting high intestinal absorption and low mutagenicity. Each task selectively improves or maintains a subset of these properties. It simulates a realistic challenge in optimizing orally active CNS agents under ADMET and pharmacological constraints.
+
+B.4Details on OOD Tasks
+1. 
+
+𝙲𝙳𝙴
+ (CARC, DRD2, hERG): These tasks target CNS drug candidates, especially antipsychotics, requiring high DRD2 inhibition. However, many such drugs are known to block the hERG potassium channel, raising serious cardiotoxicity concerns. Additionally, reducing carcinogenicity is essential for long-term drug safety. Each task may involve increasing DRD2 inhibition while reducing or preserving carcinogenicity and cardiotoxicity. This mirrors real-world lead optimization, where enhancing efficacy must be carefully balanced against major safety liabilities.
+
+2. 
+
+𝙰𝙱𝙼𝙿
+ (AMP, BBBP, MUT, PlogP): Tasks in this combination target oral CNS-targeted drug design. AMP and BBBP capture permeability at intestinal and blood-brain barriers, respectively, essential for drugs acting on the brain after oral administration. Mutagenicity must be minimized or maintained to prevent genotoxic effects, while plogP should be improved or maintained to balance lipophilicity, solubility, and synthetic accessibility. The task requires coordinated improvement of absorption and brain penetration while constraining safety and physicochemical properties, posing a non-trivial optimization challenge.
+
+3. 
+
+𝙱𝙲𝙼𝚀
+ (BBBP, CARC, MUT, QED): These tasks comprise 15 multi-objective combinations requiring improvements in BBB permeability while maintaining or minimizing toxicity (CARC, MUT) and retaining or improving drug-likeness (QED). Each task emphasizes safety-aware design for CNS-targeting molecules without degrading overall molecular quality.
+
+4. 
+
+𝙱𝙳𝙴𝚀
+ (BBBP, DRD2, hERG, QED): This combination consists of 11 diverse optimization objectives. High BBBP and DRD2 inhibition are necessary for efficacy, while low hERG inhibition is essential to avoid cardiotoxicity. QED must remain high to ensure overall molecular quality. This combination embodies the classic efficacy-safety trade-off, making it one of the most realistic and challenging multi-objective scenarios.
+
+5. 
+
+𝙷𝙻𝙼𝙿𝚀
+ (HIA, LIV, MUT, PlogP, QED): This combination includes 21 broad-spectrum ADMET-focused multi-objective tasks aimed at orally administered drugs. Each task challenges the model to find precise modifications that jointly optimize oral bioavailability and structural quality while minimizing major toxicity risks – reflecting a realistic early-phase development setting.
+
+Appendix CDiverse Instructions
+
+Figure A1 presents the prompt template used for instruction-tuning. Each prompt has three parts: (1) ‘{general instruction}’, (2) input source molecule and properties to adjust for the specific optimization task, and (3) target optimized molecule.
+
+[INST]
+{general instruction}
+%%% Input : <SMILES> {source-smiles} </SMILES>
+%%% Adjust: {adjust_i} {property_i}, ..., {adjust_k} {property_k}
+[/INST]
+%%% Response: {target-smiles}
+Figure A1:Prompt template used for instruction-tuning 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s
+
+The ‘{general instruction}’ will be replaced with one of 6 diverse task instructions, which are presented below. The first instruction is manually written, and is provided as the seed instruction to GPT-4o to generate 5 more differently phrased instructions. The last one is the hold-out instruction for inference. Below are 6 diverse instructions:
+
+1. 
+
+“Your task is to modify the given molecule to adjust specific molecular properties so that the resulting molecule satisfies the given target thresholds. Keep structural changes as minimal as possible. Your response should only contain a valid SMILES representation of the modified molecule enclosed in <SMILES> </SMILES> tags. The property values of the new molecule should meet or exceed the specified targets enclosed in <THRESHOLD> </THRESHOLD> tags."
+
+2. 
+
+“Adjust the molecular structure to ensure that each specified property reaches the corresponding threshold listed in <THRESHOLD> </THRESHOLD>. Minimize structural changes and try to maintain the core scaffold. Return the resulting molecule using <SMILES> </SMILES> tags."
+
+3. 
+
+“Alter the molecule to satisfy the provided property thresholds in <THRESHOLD> </THRESHOLD>. Preserve the core scaffold and make as few structural changes as possible. Output the SMILES of the new molecule, enclosed in <SMILES> </SMILES>."
+
+4. 
+
+“Update the given molecule so that the specified properties fall within acceptable ranges defined by the values in <THRESHOLD> </THRESHOLD>. Maintain as much of the original structure as possible. Output only the modified molecule enclosed in <SMILES> </SMILES> tags."
+
+5. 
+
+“Edit the molecular structure so that all required properties match or exceed the threshold values defined in <THRESHOLD> </THRESHOLD>. Try to retain the core scaffold. Output only the SMILES representation of the optimized molecule enclosed in <SMILES> </SMILES>."
+
+6. 
+
+“Modify the molecule to bring its properties to at least the levels defined in <THRESHOLD> </THRESHOLD>. Avoid excessive modifications and preserve the core scaffold. Output only the resulting molecule’s SMILES wrapped in <SMILES> </SMILES>."
+
+In the 2nd part of the prompt template, multiple properties to be adjusted are described via the task-specific ‘{adjust_i}’ (Figure A1). Each ‘{adjust_i}’ is randomly replaced with one of the following 5 adjustment templates for each sub-optimal property improvement:
+
+1. 
+
+"change property to be direction <THRESHOLD> value </THRESHOLD>",
+
+2. 
+
+"change the value of property to be direction <THRESHOLD> value </THRESHOLD>",
+
+3. 
+
+"change property aiming for direction <THRESHOLD> value </THRESHOLD>",
+
+4. 
+
+"change property so it is direction <THRESHOLD> value </THRESHOLD>",
+
+5. 
+
+"change property with a goal of direction <THRESHOLD> value </THRESHOLD>"
+
+Thus, 6 diverse general instruction templates and 5 diverse adjustment templates together lead to 30 different templates for instruction tuning.
+
+Property Names:
+
+We used the following names for each property where the former is used during instruction-tuning and the latter is used for evaluation in the unseen instruction setting. For other evaluation settings, we used the same property name as used in tuning.
+
+1. 
+
+AMP: “membrane permeability", “Parallel Artificial Membrane Permeability (PAMPA)"
+
+2. 
+
+BBBP: “BBB permeability", “Blood-brain barrier permeability (BBBP)"
+
+3. 
+
+CARC: “carcinogenicity", “potential to disrupt cellular metabolic processes"
+
+4. 
+
+DRD2: “DRD2 inhibition", “inhibition probability of Dopamine receptor D2"’
+
+5. 
+
+"hERG": “hERG inhibition", "potential to block hERG channel",
+
+6. 
+
+HIA: “Intestinal adsorption", “human intestinal adsorption ability"
+
+7. 
+
+"DILI": "liver injury risk", "potential to cause liver disease",
+
+8. 
+
+MUT: “Mutagenicity", “probability to induce genetic alterations (mutagenicity)"
+
+9. 
+
+PlogP: “Penalized octanol-water partition coefficient (penalized logP)", “Penalized logP which is logP penalized by synthetic accessibility score and number of large rings"
+
+10. 
+
+QED: “QED", “drug-likeness quantified by QED score"
+
+Appendix DDetails on Experimental Setup
+D.1
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s
+
+We develop specialist and generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s by instruction-tuning general-purpose LLMs on 
+𝙲
+⁢
+-
+⁢
+𝙼𝚞𝙼𝙾𝙸𝚗𝚜𝚝𝚛𝚞𝚌𝚝
+ using specific and multiple property combinations, respectively. The generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝙽
+)
+ refers to a generalist model that is trained on property combinations, each with up to 
+𝑁
+ properties. For backbone models, we use Mistral-7B-Instruct-v0.3 AI (2023) and Llama3.1-8B-Instruct Grattafiori et al. (2024), and apply parameter-efficient fine-tuning using LoRA Hu et al. (2022) through the Huggingface Transformers framework Wolf et al. (2020). All models are fine-tuned with a learning rate of 
+1
+×
+10
+−
+4
+, and a cosine scheduler with 5% warm-up. Specialist models are trained with a batch size of 32 for 10 epochs; 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝙽
+)
+ models are trained with a batch size of 128 for 5 epochs when 
+𝑁
+<=
+4
+, and for 1,800 steps when 
+𝑁
+=
+10
+. The difference in training steps/epochs is to strike a balance between training cost and overfitting. LoRA is configured with rank 16, 
+𝛼
+=
+16
+, dropout rate of 0.05, and is applied to all projection layers and the language modeling head. We conduct 0-shot evaluation for all 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s, where no in-context examples are provided. For each test molecule, we generate 20 candidate molecules using beam search decoding with a beam width of 20.
+
+Upon applying LoRA, the number of trainable parameters vary from 42M for Mistral-7B-v0.3 to 44M for Llama3.1-8B-Instruct. Training time on a single NVIDIA A100 GPU (40 GB) ranges from  1 hour for specialist models to 8–20 hours for generalist models, depending on the total number of tasks and molecule pairs – going up to 28K tasks and 1M pairs for 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝙽
+)
+ with N=10. The entire training consumed approximately 150 GPU hours.
+
+D.2Baselines
+
+In this section, we detailed the baselines selected for our comparison. Table A1 lists the sources and licenses of all the source datasets and models (i.e., artifacts) used in this work. We ensured that all artifacts were utilized in accordance with the usage guidelines specified by their original authors or licensors. For the models we developed, we have considered relevant ethical implications, which are discussed in Section 9.
+
+General-purpose LLMs:
+
+We benchmark 4 publicly available general-purpose LLMs, including 2 open-weights LLMs: Mistral-7B Instruct-v0.3 AI (2023), Llama-3.1 8B-Instruct Touvron et al. (2023), and 2 closed-weights LLMs: Claude-3.5, and GPT-4o to assess their performance in molecule optimization tasks. For open-weights LLMs, we utilize their official HuggingFace checkpoints, while for closed-weights ones, we access the checkpoints via their official APIs.
+
+We perform 0-shot and 1-shot inference (i.e., with 0 and 1 in-context examples, respectively) using the prompt templates, detailed in Appendix E.1. While few-shot prompting can improve performance, we selected 1-shot as a practical trade-off to control inference cost, especially for closed-sourced API-based models. Moreover, we found negligible performance improvement using 5-shots in our preliminary experiments. We generate up to 20 molecules per input molecule using the same generation strategy for open-source LLMs as in 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s. Since Claude and GPT do not support the beam-search decoding strategy or any customized strategy for multiple sequence generations, we generate only one molecule per input prompt.
+
+Foundational LLMs for Chemistry:
+
+We adopt 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+, the Mistral-7B variant of 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+, as the foundational LLM for chemistry due to its strong performance across diverse molecular tasks. In comparison to other instruction-tuned LLMs for chemistry, such as 
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+ Zhao et al. (2025), MolInst Fang et al. (2024) and ChemLLM Zhang et al. (2024), 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ consistently achieves state-of-the-art results. For evaluation, we adopt 0-shot inference. Our preliminary experiments indicated that incorporating in-context examples did not lead to consistent improvements, rather impacted performance. Furthermore, we employ a simplified prompt format (as shown in Appendix E.2) after observing that 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+ struggles to follow more complex and structured instruction formats. For 
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+, we use 0-shot inference using the same prompt template and generation configuration as of general-purpose LLMs.
+
+Non-LLM Domain-expert Methods:
+
+Existing non-LLM methodsFu et al. (2021); Sun et al. (2022); Angelo et al. (2023); Kim et al. (2024) rely on genetic algorithms or reinforcement learning. These methods typically require carefully curated fitness or reward functions to balance multiple properties. Such functions are often difficult to design and require significant domain expertise, limiting their flexibility and generalizability.
+
+Furthermore, these methods follow a fundamentally different experimental setting: given an initial pool of candidates, these methods iteratively modify molecules based on oracle feedback. This often leads to generating molecules with entirely new scaffolds. In contrast, our setting closely aligns with lead optimization in drug discovery, where the goal is to minimally modify an input molecule while preserving its core scaffold.
+
+D.3Evaluation Metrics
+
+We adopt multiple evaluation metrics to comprehensively assess model performance. The metrics are defined as follows:
+
+1. 
+
+Success Rate (
+𝚂𝚁
+): 
+𝚂𝚁
+ denotes the proportion of test cases where at least one of the 20 generated candidate molecules satisfies all specified property objectives – i.e., improving all sub-optimal properties while preserving all near-optimal ones. When multiple candidates are optimized, the molecule exhibiting the highest cumulative improvement is selected for evaluation. A higher 
+𝚂𝚁
+ reflects the model’s effectiveness in achieving task-specific optimization goals.
+
+2. 
+
+Strict Success Rate (
+𝚂𝚁
+𝛩
+): 
+𝚂𝚁
+𝛩
+– a stricter variant of 
+𝚂𝚁
+ – measures the proportion of test cases where at least one generated molecule not only improves all sub-optimal properties but also brings each of them above the pharmaceutically relevant threshold 
+Θ
+𝑝
+, while still preserving all near-optimal properties within their respective 
+Δ
+𝑝
+ bounds. This metric reflects whether the model can generate molecules with desirable properties as specified.
+
+3. 
+
+Validity (
+𝚅𝚊𝚕
+): Validity refers to the percentage of test instances for which at least one of the generated molecules is chemically valid, determined via successful parsing by RDKit. High 
+𝚅𝚊𝚕
+ensures the model’s ability to generate syntactically correct and chemically valid structures.
+
+4. 
+
+Similarity (
+𝚂𝚒𝚖
+): 
+𝚂𝚒𝚖
+ measures the average Tanimoto similarity between optimized and input molecules based on binary Morgan fingerprints (with radius of 2 and dimension of 2048). Higher 
+𝚂𝚒𝚖
+ indicates better preservation of the similarity constraint – a key requirement in lead optimization, where maintaining the core molecular scaffold is essential.
+
+5. 
+
+Novelty (
+𝙽𝚘𝚟
+): Novelty quantifies the fraction of optimized molecules that are not present in the training set. This indicates the model’s ability to generate novel and previously unseen drug candidates, crucial for exploration in drug discovery pipelines.
+
+6. 
+
+Synthetic Accessibility Score (
+𝚂𝙰𝚂
+): 
+𝚂𝙰𝚂
+ evaluates how easy a molecule is to synthesize, with scores ranging from 1 (easily synthesizable) to 10 (difficult to synthesize) Ertl and Schuffenhauer (2009a). Lower scores indicate simpler, more synthesizable molecules.
+
+7. 
+
+Relative Improvement (
+𝚁𝙸
+): 
+𝚁𝙸
+ is computed as the average relative gain in each sub-optimal property compared to the input molecule. This metric reflects the magnitude of property-level improvements achieved by the model. Formally, for a task improving 
+𝒫
+𝚒
+ properties, 
+𝚁𝙸
+ is computed as the average of relative change (
+𝚁𝙸
+p) in each property 
+𝑝
+∈
+𝒫
+𝚒
+ as:
+
+	
+𝚁𝙸
+=
+∑
+𝑝
+∈
+𝒫
+𝚒
+𝚁𝙸
+𝑝
+|
+𝒫
+𝚒
+|
+,
+	
+
+where 
+𝚁𝙸
+p is computed as:
+
+	
+𝚁𝙸
+𝑝
+=
+𝔻
+⁢
+[
+𝑝
+]
+⁢
+(
+𝑝
+⁢
+(
+𝑀
+𝑦
+)
+−
+𝑝
+⁢
+(
+𝑀
+𝑥
+)
+)
+𝑝
+⁢
+(
+𝑀
+𝑥
+)
+,
+	
+
+where 
+𝔻
+⁢
+[
+𝑝
+]
+ is an indicator function denoting whether higher scores of 
+𝑝
+ is desirable, 
+𝑝
+⁢
+(
+𝑀
+𝑥
+)
+ and 
+𝑝
+⁢
+(
+𝑀
+𝑦
+)
+ denote the score of property 
+𝑝
+ in the input molecule 
+𝑀
+𝑥
+ and generated molecule 
+𝑀
+𝑦
+, respectively.
+
+8. 
+
+Average Property Score (
+𝙰𝙿𝚂
+): 
+𝙰𝙿𝚂
+ is computed as the average property score for each molecular property across all successfully optimized molecules. Higher or lower 
+����𝙿𝚂
+, depending on the desired direction for each property, indicates that the model consistently generates better molecules with property scores aligned with pharmaceutical objectives.
+
+Appendix EPrompt Templates
+
+The prompt templates for general-purpose LLMs and for 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+ are provided below.
+
+E.1Prompt Template for General-purpose LLMs
+
+We use a structured and detailed prompt template with a system prompt, task instruction, and in-context examples for few-shot prompting. Figure A2 shows an example.
+
+<<SYS>>
+You are an expert medicinal chemist specializing in molecular optimization. You understand how structural modifications affect key ADMET properties and inhibitions of common receptor targets like DRD2.
+<</SYS>>
+[INST]
+Your task is to modify the given molecule to adjust specific molecular properties while keeping structural changes as minimal as possible. Use the examples (if provided) as a guide. Your response should only contain a valid SMILES representation of the modified molecule enclosed with <SMILES> </SMILES> tag.
+Examples:
+%%% Input : <SMILES> O=C(Cc1cccc([N+](=O)[O-])c1)NC1CCN(Cc2ccccc2)CC1 </SMILES>
+%%% Adjust: increase DRD2 inhibition with a goal of at least <THRESHOLD> 0.54 </THRESHOLD>, decrease Mutagenicity with a goal of at most <THRESHOLD> 0.1 </THRESHOLD> and increase QED aiming for at least <THRESHOLD> 0.89 </THRESHOLD> while keeping Intestinal adsorption unchanged.
+%%% Response: <SMILES> O=C(Cc1ccc(O)cc1)NC1CCN(Cc2ccccc2)CC1 </SMILES>
+Task:
+%%% Input : <SMILES> C#Cc1ccc(C2CC3CCC(C2C(=O)OC)N3C)cc1 </SMILES>
+%%% Adjust: decrease Mutagenicity with a goal of at most <THRESHOLD> 0.2 </THRESHOLD>, increase QED with a goal of at least <THRESHOLD> 0.8 </THRESHOLD> and increase the value of DRD2 inhibition to be at least <THRESHOLD> 0.2 </THRESHOLD> while keeping Intestinal adsorption unchanged.
+[/INST]
+%%% Response:
+Figure A2:An example of a prompt used for general-purpose LLMs
+E.2Prompt Template for 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+
+Unlike general-purpose language models, 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+ was instruction-tuned on a range of chemistry-specific tasks using a dedicated prompt structure. In our preliminary experiments, we found that applying the general-purpose prompt format led to suboptimal performance, as 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+ often failed to interpret the task correctly. To address this, we adopted a simplified prompt format that omits the system message and does not explicitly separate the instruction, input, and expected output. Additionally, we restrict our evaluation of 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+ to 0-shot inference only. Figure A3 illustrates the simplified prompt used for the same task as above.
+
+Modify the molecule <SMILES> C#Cc1ccc(C2CC3CCC(C2C(=O)OC)N3C)cc1 <SMILES> to decrease the value of Mutagenicity to be at most <THRESHOLD> 0.2 </THRESHOLD>, increase QED to be at least <THRESHOLD> 0.8 </THRESHOLD> and increase DRD2 inhibition to be at least <THRESHOLD> 0.2 </THRESHOLD> while keeping Intestinal adsorption unchanged.
+%%% Response:
+Figure A3:An example of a prompt used for 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+Table A1:Licenses and Sources of Artifacts
+Artifact	
+Source
+	
+License Type
+	Accessibility
+Modof	
+https://github.com/ziqi92/Modof
+	
+PolyForm Noncommercial License 1.0.0
+	Open Source
+
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	
+https://huggingface.co/datasets/osunlp/SMolInstruct
+	
+Creative Commons Attribution 4.0
+	Checkpoint
+
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+𝙻𝚕𝚊𝚖𝚊
+	
+https://huggingface.co/OpenDFM/ChemDFM-v1.5-8B
+	
+GNU Affero General Public License v3.0
+	Checkpoint
+Claude 3.5 (Sonnet)	
+https://docs.anthropic.com/claude/reference/getting-started-with-the-api
+	
+Proprietary
+	API
+GPT-4o	
+https://openai.com/api/
+	
+Proprietary
+	API
+Llama-3.1 8B-Instruct	
+https://huggingface.co/meta-llama/Llama-3.1-8B-Instruct
+	
+Llama 3.1 Community
+	Checkpoint
+Mistral-7B-Instruct-v0.3	
+https://huggingface.co/mistralai/Mistral-7B-Instruct-v0.3
+	
+Apache license 2.0
+	Checkpoint
+Appendix FCase Studies
+F.1Case from 
+𝙰𝙲𝙴𝙿
+
+Figure 4(a) and Figure 4(b) show optimization examples generated by 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ and 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ on the IND task 
+𝙰𝙲𝙴𝙿
+. The hit molecule features a central urea scaffold with a carboxamide and a morpholine ring. The goal is to improve AMP and PlogP while maintaining CARC and hERG.
+
+(a)
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ optimization
+(b)
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ optimization
+Figure A4:An example from 
+𝙰𝙲𝙴𝙿
+. Modifications are highlighted in red.
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ accomplishes this by replacing the morpholine with a para-chlorophenyl group (Figure 4(a)). This modification eliminates a polar heterocycle and introduces a planar, lipophilic aromatic ring bearing a chlorine atom. This leads to notable improvements in AMP (+0.29) and PlogP (+0.85), while CARC and hERG remain within acceptable ranges. The increased hydrophobicity introduced by the chlorinated aromatic ring contributes to a higher PlogP, as aromatic chlorides are known to enhance lipophilicity due to both the non-polar nature of the phenyl group and the electron-withdrawing effect of chlorine Hansch et al. (1995). The rigid aromatic system may reduce the molecule’s conformational flexibility, which in turn lowers conformational entropy. This structural constraint can limit the number of unintended binding interactions, thereby reducing the likelihood of off-target liabilities Meanwell (2011b, 2016)
+
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+’s modification replaces the morpholine with a pyrrolidine ring. This change maintains a basic nitrogen atom but removes the oxygen, slightly reducing polarity compared to morpholine. Although this approach achieves a moderate PlogP improvement (+0.63), it shows a concerning increase in hERG liability (+0.16). The pyrrolidine ring, while structurally similar to morpholine (Figure 4(b)), introduces greater basicity and conformational flexibility. These properties are known risk factors for hERG channel binding in medicinal chemistry, explaining the less favorable safety profile Cavalli et al. (2002).
+
+(a)
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ optimization
+(b)
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ optimization
+Figure A5:An example from 
+𝙰𝙱𝙼𝙿
+. Modifications are highlighted in red.
+F.2Case from 
+𝙰𝙱𝙼𝙿
+
+Figure 5(a) and Figure 5(b) present optimization examples produced by 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ and 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ on the OOD task 
+𝙰𝙱𝙼𝙿
+. The hit molecule is a symmetric tri-amide structure, composed of three carbonyl linkers connecting aromatic and aliphatic moieties. The goal is to improve BBBP, while keeping AMP, MUT, and PlogP stable.
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ introduces a substantial simplification by collapsing the tri-amide backbone into a more compact structure containing a single central amide and two substituted aromatic rings (Figure 5(a)). This transformation removes several polar functional groups and incorporates lipophilic features such as methyl and aryl substitutions. These changes are well-aligned with medicinal chemistry strategies for enhancing membrane permeability – primarily through increased lipophilicity and reduced polarity Meanwell (2011a); Leeson and Springthorpe (2007). As a result, 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ achieves a favorable outcome, yielding a significant improvement in BBBP (+0.15), along with a modest increase in PlogP (+0.19), while keeping AMP and MUT values stable.
+
+In contrast, 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ applies a conservative modification by retaining the tri-amide scaffold and appending an isopropyl group to the left-hand side of the molecule (Figure 5(b)). This change preserves the molecule’s original polarity and structural complexity, while introducing additional steric bulk. Crucially, it fails to reduce polarity or increase hydrophobicity – both essential for maintaining or improving PlogP Ertl and Schuffenhauer (2009b). As a result, despite a small gain in BBBP (+0.11), the model suffers a substantial drop in PlogP (–0.46) and an increase in toxicity (MUT), indicating an unfavorable optimization outcome.
+
+Appendix GComplete Experimental Results
+G.1IND Evaluation
+
+Tables A3, A4, A5, A6 and A7 presents the performance comparison of 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s with general-purpose LLMs and 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ under all evaluation metrics for each IND task.
+
+Table A2 presents the overall performance comparison of 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s with all baselines under the strict success criteria. This requires each sub-optimal property to exceed its predefined pharmaceutically relevant threshold, 
+Θ
+𝑝
+, in the optimized molecule. We use 
+Θ
+𝑝
+ to reflect realistic drug design objectives, where each property is expected to reach a clinically meaningful level. However, this is a highly challenging setting, particularly because our evaluation involves only a single-step molecule modification. Starting molecules may be significantly sub-optimal, and a single structural change may not be sufficient to reach such high thresholds. This explains the significantly lower success rates for all models compared to the looser success criteria in Table 3.
+
+Table A2:Overall Performance in IND Tasks with stricter success criteria
+Model	
+𝙱𝙿𝚀
+		
+𝙴𝙻𝚀
+		
+𝙰𝙲𝙴𝙿
+		
+𝙱𝙳𝙿𝚀
+		
+𝙳𝙷𝙼𝚀
+
+
+𝚂𝚁
+𝛩
+↑ 	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+𝛩
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+𝛩
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+𝛩
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+𝛩
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑
+General-purpose LLMs
+Mistral (0-shot)	3.40	0.71	1.60		3.40	0.70	0.38		2.80	0.70	0.88		0.00	-	-		0.00	-	-
+Llama (0-shot)	3.80	0.69	0.39		2.20	0.69	0.27		1.00	0.71	0.53		0.00	-	-		0.20	0.75	3.00
+Claude-3.5 (0-shot)	4.40	0.65	0.56		3.00	0.63	0.40		1.60	0.60	0.72		0.00	-	-		0.00	-	-
+GPT-4o (0-shot)	1.60	0.73	0.48		1.40	0.67	0.33		1.60	0.72	0.34		0.00	-	-		0.40	0.71	2.51
+Mistral (1-shot)	14.20	0.53	1.45		16.20	0.57	0.49		10.20	0.54	1.31		3.40	0.32	18.68		3.40	0.39	3.87
+Llama (1-shot)	6.40	0.63	0.62		4.80	0.61	0.39		3.00	0.63	0.47		0.40	0.15	18.71		2.20	0.28	14.00
+Claude-3.5 (1-shot)	9.20	0.59	0.95		3.20	0.63	0.42		3.60	0.73	0.72		0.60	0.38	4.16		0.40	0.69	2.73
+GPT-4o (1-shot)	2.60	0.70	0.45		2.00	0.67	0.28		1.20	0.73	0.25		0.00	-	-		1.00	0.71	2.72
+Foundational LLMs for Chemistry
+LlaSMol-M	14.80	0.61	0.88		17.60	0.60	0.48		10.80	0.62	0.67		0.60	0.68	9.42		1.40	0.70	4.12
+
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+𝙻𝚕𝚊𝚖𝚊
+	3.20	0.63	0.33		3.00	0.65	0.38		1.40	0.69	0.40		0.20	0.55	0.78		0.60	0.81	5.44
+Specialist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙽
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	25.40	0.51	2.57		28.80	0.51	0.56		28.00	0.50	4.00		9.40	0.35	13.24		6.40	0.52	9.92
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙽
+𝙻𝚕𝚊𝚖𝚊
+	29.60	0.53	2.06		31.40	0.50	0.58		31.40	0.50	3.14		4.60	0.48	16.89		4.20	0.65	10.68
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝚂𝚙𝚎𝚌
+ (%)	100.0	-13.1	134.1		78.4	-16.7	20.8		190.7	-19.4	368.7		176.5	9.4	-29.1		88.2	33.3	156.3
+Generalist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝙽
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	27.60	0.59	2.43		23.40	0.62	0.51		31.20	0.57	3.42		5.40	0.55	11.30		9.00	0.54	11.53
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝙽
+)
+𝙻𝚕𝚊𝚖𝚊
+	30.60	0.57	2.15		25.60	0.60	0.51		34.40	0.55	2.77		6.40	0.50	19.46		6.80	0.60	13.35
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	32.60	0.59	2.32		32.00	0.57	0.55		23.40	0.58	1.88		3.80	0.59	13.26		4.80	0.64	11.14
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+	32.40	0.54	2.59		27.60	0.56	0.54		25.20	0.56	3.11		5.00	0.51	22.70		5.40	0.56	13.70
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+ (%)	120.3	-3.3	163.6		81.8	-5.0	14.6		218.5	-11.3	313.4		88.2	56.2	4.2		164.7	38.5	197.9
+• 
+
+↑ and ↓ indicate whether a higher or lower value of the metric is preferred, respectively. For each task, we underline the best baseline performance and highlight in bold the best performing model for each metric. 
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝚂𝚙𝚎𝚌
+ and 
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+ represent the relative percentage improvement from the best specialist LLM and best generalist LLM over the best baseline, respectively. The best model in each group is selected based on 
+𝚂𝚁
+ for each task.
+
+Table A3:Overall Performance on 
+𝙱𝙿𝚀
+Model	
+𝚂𝚁
+↑	
+𝚅𝚊𝚕
+↑	
+𝚂𝚒𝚖
+↑	
+𝙽𝚘𝚟
+↑	
+𝚂𝙰𝚂
+↓	
+𝚁𝙸
+↑	
+𝙰𝙿𝚂
+
+BBBP↑ 	PlogP↑	QED↑
+General-purpose LLMs
+Mistral (0-shot)	28.80	85.80	0.75	100.00	2.87	1.24	0.92	0.41	0.77
+Llama (0-shot)	33.60	99.00	0.70	100.00	2.86	0.78	0.92	0.65	0.76
+Claude-3.5 (0-shot)	51.80	96.80	0.68	99.61	2.75	0.89	0.91	0.70	0.75
+GPT-4o (0-shot)	30.20	88.00	0.72	100.00	2.70	0.55	0.90	0.65	0.76
+Mistral (1-shot)	72.80	99.20	0.63	97.53	2.58	1.26	0.91	1.07	0.77
+Llama (1-shot)	49.60	100.00	0.68	99.19	2.71	0.95	0.91	0.89	0.75
+Claude-3.5 (1-shot)	61.80	96.60	0.65	100.00	2.68	1.31	0.93	0.90	0.77
+GPT-4o (1-shot)	28.60	86.20	0.74	100.00	2.76	0.77	0.90	0.70	0.76
+Foundational LLMs for Chemistry
+
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ 	78.20	100.00	0.64	99.74	2.65	0.92	0.91	0.87	0.77
+
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+𝙻𝚕𝚊𝚖𝚊
+	27.00	92.00	0.66	99.26	2.82	0.65	0.93	0.68	0.77
+Specialist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝟹
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	71.00	98.40	0.57	98.87	2.45	2.59	0.93	1.51	0.79
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝟹
+𝙻𝚕𝚊𝚖𝚊
+ 	84.20	100.00	0.58	99.05	2.46	2.09	0.92	1.44	0.79
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝚂𝚙𝚎𝚌
+	7.7	0.0	-9.4	-0.7	7.2	127.2	1.1	65.5	2.6
+Generalist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟹
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	84.80	100.00	0.63	99.06	2.46	2.64	0.92	1.47	0.78
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟹
+)
+𝙻𝚕𝚊𝚖𝚊
+	88.80	100.00	0.62	99.10	2.38	2.16	0.92	1.48	0.79
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ 	89.40	99.00	0.62	98.43	2.49	2.30	0.93	1.39	0.79
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+	79.40	88.80	0.57	97.48	2.42	2.67	0.93	1.56	0.79
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+	14.3	-1.0	-3.1	-1.3	6.0	150.0	2.2	59.8	2.6
+• 
+
+↑ and ↓ indicate whether a higher or lower value of the metric is preferred, respectively. For each task, we underline the best baseline performance and highlight in bold the best performing model for each metric. 
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝚂𝚙𝚎𝚌
+ and 
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+ represent the relative percentage improvement from the best specialist LLM and best generalist LLM over the best baseline, respectively. The best model in each group is selected based on 
+𝚂𝚁
+ for each task.
+
+Table A4:Overall Performance on 
+𝙴𝙻𝚀
+Model	
+𝚂𝚁
+↑	
+𝚅𝚊𝚕
+↑	
+𝚂𝚒𝚖
+↑	
+𝙽𝚘𝚟
+↑	
+𝚂𝙰𝚂
+↓	
+𝚁𝙸
+↑	
+𝙰𝙿𝚂
+
+hERG↓ 	LIV↓	QED↑
+General-purpose LLMs
+Mistral (0-shot)	21.60	89.20	0.72	100.00	2.82	0.16	0.37	0.55	0.77
+Llama (0-shot)	16.60	97.40	0.74	100.00	2.90	0.10	0.44	0.56	0.80
+Claude-3.5 (0-shot)	20.00	96.40	0.64	100.00	2.67	0.20	0.41	0.60	0.76
+GPT-4o (0-shot)	16.60	90.80	0.72	100.00	2.83	0.10	0.39	0.53	0.74
+Mistral (1-shot)	74.80	99.80	0.59	94.92	2.77	0.28	0.38	0.55	0.78
+Llama (1-shot)	36.80	99.40	0.68	97.83	2.90	0.15	0.45	0.56	0.77
+Claude-3.5 (1-shot)	29.20	97.60	0.63	100.00	2.73	0.21	0.48	0.58	0.76
+GPT-4o (1-shot)	19.60	90.00	0.72	100.00	2.85	0.12	0.46	0.53	0.76
+Foundational LLMs for Chemistry
+
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ 	81.40	99.80	0.62	99.26	2.71	0.28	0.38	0.56	0.77
+
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+𝙻𝚕𝚊𝚖𝚊
+	15.00	91.20	0.68	100.00	2.91	0.19	0.38	0.52	0.79
+Specialist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝟹
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	81.80	99.40	0.55	99.27	2.85	0.39	0.32	0.46	0.79
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝟹
+𝙻𝚕𝚊𝚖𝚊
+ 	85.40	100.00	0.53	99.53	2.87	0.41	0.29	0.46	0.79
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝚂𝚙𝚎𝚌
+	4.9	0.2	-14.5	0.3	-5.9	46.4	23.7	17.9	2.6
+Generalist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟹
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	83.20	99.80	0.63	98.80	2.64	0.33	0.33	0.53	0.78
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟹
+)
+𝙻𝚕𝚊𝚖𝚊
+ 	90.80	100.00	0.63	98.90	2.60	0.34	0.33	0.52	0.80
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	88.40	99.80	0.59	99.55	2.64	0.41	0.29	0.50	0.81
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+	79.00	90.60	0.56	99.49	2.58	0.41	0.30	0.48	0.81
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+	11.5	0.2	1.6	-0.4	4.1	21.4	13.2	7.1	3.9
+• 
+
+The metrics, notations, and formatting have the same meanings as those in Table A3.
+
+Table A5:Overall Performance on 
+𝙰𝙲𝙴𝙿
+Model	
+𝚂𝚁
+↑	
+𝚅𝚊𝚕
+↑	
+𝚂𝚒𝚖
+↑	
+𝙽𝚘𝚟
+↑	
+𝚂𝙰𝚂
+↓	
+𝚁𝙸
+↑	
+𝙰𝙿𝚂
+	
+AMP↑ 	CARC↓	hERG↓	PlogP↑
+General-purpose LLMs
+Mistral (0-shot)	26.20	87.20	0.75	100.00	2.77	1.10	0.90	0.18	0.38	0.70
+Llama (0-shot)	17.20	98.00	0.74	100.00	2.74	0.69	0.90	0.20	0.47	0.76
+Claude-3.5 (0-shot)	29.60	96.20	0.71	100.00	2.78	0.69	0.91	0.17	0.38	0.64
+GPT-4o (0-shot)	22.20	91.40	0.74	99.10	2.77	0.52	0.90	0.17	0.36	0.54
+Mistral (1-shot)	63.80	99.80	0.64	95.92	2.56	1.03	0.92	0.18	0.43	0.92
+Llama (1-shot)	40.20	99.00	0.70	98.51	2.64	1.12	0.92	0.20	0.46	0.87
+Claude-3.5 (1-shot)	32.60	96.60	0.71	100.00	2.74	1.24	0.94	0.16	0.42	0.60
+GPT-4o (1-shot)	23.00	88.80	0.76	100.00	2.79	1.09	0.93	0.17	0.40	0.63
+Foundational LLMs for Chemistry
+
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	68.60	100.00	0.66	99.71	2.65	1.00	0.93	0.17	0.43	0.90
+
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+𝙻𝚕𝚊𝚖𝚊
+	22.00	93.00	0.72	100.00	2.85	1.03	0.93	0.16	0.44	0.84
+Specialist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝟺
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	85.60	100.00	0.54	99.53	2.39	2.46	0.95	0.14	0.33	1.24
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝟺
+𝙻𝚕𝚊𝚖𝚊
+	88.00	99.80	0.54	99.55	2.38	2.24	0.95	0.14	0.34	1.25
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝚂𝚙𝚎𝚌
+	28.3	-0.2	-18.2	-0.2	10.2	124.0	2.2	17.6	20.9	38.9
+Generalist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟺
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	86.60	100.00	0.60	98.61	2.38	2.34	0.96	0.15	0.36	1.25
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟺
+)
+𝙻𝚕𝚊𝚖𝚊
+	92.80	99.80	0.58	98.92	2.34	2.22	0.95	0.15	0.35	1.26
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	74.60	100.00	0.61	99.20	2.44	1.92	0.95	0.13	0.35	1.11
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+	72.60	93.60	0.57	98.62	2.38	2.27	0.96	0.15	0.38	1.33
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+	35.3	-0.2	-12.1	-0.8	11.7	122.0	2.2	11.8	18.6	40.0
+• 
+
+The metrics, notations, and formatting have the same meanings as those in Table A3.
+
+Table A6:Overall Performance on 
+𝙱𝙳𝙿𝚀
+Model	
+𝚂𝚁
+↑	
+𝚅𝚊𝚕
+↑	
+𝚂𝚒𝚖
+↑	
+𝙽𝚘𝚟
+↑	
+𝚂𝙰𝚂
+↓	
+𝚁𝙸
+↑	
+𝙰𝙿𝚂
+	
+BBBP↑ 	DRD2↑	PlogP↑	QED↑
+General-purpose LLMs
+Mistral (0-shot)	2.40	75.60	0.72	100.00	2.83	0.49	0.96	0.09	0.66	0.82
+Llama (0-shot)	8.80	97.00	0.72	100.00	3.24	1.67	0.96	0.06	0.03	0.79
+Claude-3.5 (0-shot)	11.20	96.80	0.67	100.00	2.78	1.80	0.93	0.09	0.60	0.78
+GPT-4o (0-shot)	4.20	84.80	0.72	100.00	2.92	3.98	0.93	0.07	0.51	0.82
+Mistral (1-shot)	21.60	99.20	0.59	92.59	2.65	4.76	0.94	0.18	0.94	0.80
+Llama (1-shot)	14.40	99.40	0.63	91.67	3.01	2.65	0.94	0.11	0.63	0.78
+Claude-3.5 (1-shot)	15.60	95.20	0.58	100.00	2.66	3.99	0.94	0.11	1.26	0.80
+GPT-4o (1-shot)	5.60	87.20	0.68	100.00	2.65	3.47	0.95	0.09	1.09	0.85
+Foundational LLMs for Chemistry
+
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	22.60	100.00	0.68	100.00	2.85	2.22	0.93	0.09	0.63	0.78
+
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+𝙻𝚕𝚊𝚖𝚊
+	6.20	93.00	0.67	100.00	2.85	3.51	0.92	0.07	0.64	0.80
+Specialist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝟺
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	56.60	100.00	0.50	97.88	2.45	5.48	0.95	0.22	1.25	0.79
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝟺
+𝙻𝚕𝚊𝚖𝚊
+	43.60	99.80	0.58	99.08	2.52	4.85	0.95	0.16	1.14	0.79
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝚂𝚙𝚎𝚌
+	150.4	0.0	-26.5	-2.1	14.0	146.8	2.2	144.4	98.4	1.3
+Generalist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟺
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	50.60	100.00	0.58	99.21	2.51	4.93	0.95	0.17	1.23	0.79
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟺
+)
+𝙻𝚕𝚊𝚖𝚊
+	51.00	100.00	0.58	98.43	2.49	5.40	0.95	0.17	1.19	0.78
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	48.40	99.40	0.58	99.17	2.55	5.05	0.95	0.16	1.22	0.79
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+	42.60	88.60	0.55	98.59	2.47	5.89	0.94	0.17	1.37	0.79
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+	125.7	0.0	-14.7	-1.6	12.6	143.2	2.2	88.9	88.9	0.0
+• 
+
+The metrics, notations, and formatting have the same meanings as those in Table A3.
+
+Table A7:Overall Performance on 
+𝙳𝙷𝙼𝚀
+Model	
+𝚂𝚁
+↑	
+𝚅𝚊𝚕
+↑	
+𝚂𝚒𝚖
+↑	
+𝙽𝚘𝚟
+↑	
+𝚂𝙰𝚂
+↓	
+𝚁𝙸
+↑	
+𝙰𝙿𝚂
+
+DRD2↑ 	HIA↑	MUT↓	QED↑
+General-purpose LLMs
+Mistral (0-shot)	4.80	86.80	0.71	100.00	2.88	0.76	0.05	1.00	0.29	0.80
+Llama (0-shot)	6.00	97.40	0.73	100.00	3.09	1.35	0.06	1.00	0.28	0.79
+Claude-3.5 (0-shot)	5.20	95.20	0.63	100.00	2.73	1.84	0.10	1.00	0.20	0.75
+GPT-4o (0-shot)	5.80	87.80	0.72	100.00	2.89	0.88	0.07	1.00	0.22	0.82
+Mistral (1-shot)	25.60	99.80	0.55	86.72	2.89	1.89	0.18	1.00	0.21	0.78
+Llama (1-shot)	13.80	99.40	0.56	85.51	3.06	3.39	0.18	1.00	0.24	0.79
+Claude-3.5 (1-shot)	8.40	95.20	0.65	100.00	2.77	1.38	0.12	1.00	0.21	0.78
+GPT-4o (1-shot)	5.60	87.40	0.71	100.00	2.78	1.22	0.10	1.00	0.22	0.81
+Foundational LLMs for Chemistry
+
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	24.80	100.00	0.62	100.00	2.93	1.44	0.08	0.99	0.20	0.78
+
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+𝙻𝚕𝚊𝚖𝚊
+	6.80	86.40	0.67	100.00	3.03	1.72	0.07	1.00	0.17	0.82
+Specialist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝟺
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	44.60	99.80	0.57	99.10	2.81	2.96	0.14	0.99	0.19	0.78
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝟺
+𝙻𝚕𝚊𝚖𝚊
+	35.40	100.00	0.65	100.00	2.73	2.63	0.12	0.99	0.20	0.79
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝚂𝚙𝚎𝚌
+	74.2	0.0	3.6	14.3	2.8	56.6	-22.2	-1.0	9.5	0.0
+Generalist LLMs
+
+��𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟺
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	53.40	100.00	0.59	99.25	2.76	3.26	0.15	0.99	0.19	0.78
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟺
+)
+𝙻𝚕𝚊𝚖𝚊
+	50.40	100.00	0.59	100.00	2.67	3.28	0.13	0.99	0.19	0.79
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	52.20	99.60	0.61	100.00	2.76	2.24	0.12	0.99	0.19	0.79
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+	41.80	83.20	0.57	100.00	2.65	3.32	0.15	0.99	0.20	0.79
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+	108.6	0.2	7.3	14.4	4.5	72.5	-16.7	-1.0	9.5	0.0
+• 
+
+The metrics, notations, and formatting have the same meanings as those in Table A3.
+
+G.2OOD Evaluation
+
+Tables A8, A9, A10, A11 and A12 presents the performance comparison of 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s with general-purpose LLMs and 
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ under all evaluation metrics for each OOD task.
+
+Table A8:Overall Performance on 
+𝙲𝙳𝙴
+Model	
+𝚂𝚁
+↑	
+𝚅𝚊𝚕
+↑	
+𝚂𝚒𝚖
+↑	
+𝙽𝚘𝚟
+↑	
+𝚂𝙰𝚂
+↓	
+𝚁𝙸
+↑	
+𝙰𝙿𝚂
+
+CARC↓ 	DRD2↑	hERG↓
+General-purpose LLMs
+Mistral (0-shot)	3.00	86.00	0.73	100.00	3.13	1.33	0.15	0.14	0.65
+Llama (0-shot)	6.80	96.60	0.68	100.00	3.32	0.77	0.20	0.06	0.57
+Claude-3.5 (0-shot)	6.80	97.80	0.70	100.00	2.98	1.07	0.16	0.08	0.52
+GPT-4o (0-shot)	3.80	89.80	0.74	100.00	3.01	1.56	0.15	0.05	0.39
+Mistral (1-shot)	30.60	99.60	0.62	93.46	3.00	1.66	0.15	0.09	0.50
+Llama (1-shot)	18.20	99.40	0.55	76.92	3.50	1.51	0.14	0.12	0.47
+Claude-3.5 (1-shot)	8.40	98.40	0.66	100.00	2.91	1.09	0.12	0.08	0.47
+GPT-4o (1-shot)	7.00	88.20	0.72	100.00	3.10	1.04	0.16	0.05	0.53
+Foundational LLMs for Chemistry
+
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	29.80	99.80	0.61	97.99	2.79	1.28	0.14	0.06	0.46
+
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+𝙻𝚕𝚊𝚖𝚊
+	8.20	90.60	0.64	100.00	3.16	0.84	0.17	0.08	0.53
+Generalist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+ 	39.80	98.60	0.58	100.00	2.85	1.66	0.11	0.08	0.42
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+	33.20	86.80	0.55	100.00	2.86	1.50	0.11	0.08	0.48
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+	30.1	-1.0	-6.5	7.0	5.0	0.0	26.7	-11.1	16.0
+• 
+
+The metrics, notations, and formatting have the same meanings as those in Table A3.
+
+Table A9:Overall Performance on 
+𝙰𝙱𝙼𝙿
+Model	
+𝚂𝚁
+↑	
+𝚅𝚊𝚕
+↑	
+𝚂𝚒𝚖
+↑	
+𝙽𝚘𝚟
+↑	
+𝚂𝙰𝚂
+↓	
+𝚁𝙸
+↑	
+𝙰𝙿𝚂
+	
+AMP↑ 	BBBP↑	MUT↓	PlogP↑
+General-purpose LLMs
+Mistral (0-shot)	23.00	83.00	0.77	100.00	2.76	0.93	0.90	0.87	0.24	0.86
+Llama (0-shot)	44.60	98.40	0.71	100.00	2.85	0.61	0.92	0.90	0.25	1.17
+Claude-3.5 (0-shot)	43.60	96.20	0.70	100.00	2.73	0.80	0.95	0.89	0.24	0.81
+GPT-4o (0-shot)	27.00	87.40	0.73	100.00	2.72	0.51	0.93	0.89	0.25	0.93
+Mistral (1-shot)	73.20	99.60	0.64	94.81	2.62	1.09	0.93	0.90	0.23	1.10
+Llama (1-shot)	60.80	99.60	0.70	99.01	2.76	0.83	0.92	0.89	0.24	1.02
+Claude-3.5 (1-shot)	45.20	96.40	0.64	100.00	2.67	0.87	0.95	0.91	0.23	1.04
+GPT-4o (1-shot)	34.40	87.80	0.74	100.00	2.73	0.65	0.93	0.89	0.28	1.03
+Foundational LLMs for Chemistry
+
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	72.40	100.00	0.67	100.00	2.75	0.78	0.94	0.89	0.24	0.93
+
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+𝙻𝚕𝚊𝚖𝚊
+	39.60	92.40	0.67	100.00	2.95	0.98	0.94	0.89	0.23	1.40
+Generalist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	86.60	99.40	0.63	98.85	2.48	1.68	0.95	0.92	0.20	1.63
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+	79.60	89.60	0.58	98.99	2.42	1.81	0.96	0.91	0.19	1.81
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+	18.3	-0.2	-1.6	4.3	5.3	54.1	2.2	2.2	13.0	48.2
+• 
+
+The metrics, notations, and formatting have the same meanings as those in Table A3.
+
+Table A10:Overall Performance on 
+𝙱𝙲𝙼𝚀
+Model	
+𝚂𝚁
+↑	
+𝚅𝚊𝚕
+↑	
+𝚂𝚒𝚖
+↑	
+𝙽𝚘𝚟
+↑	
+𝚂𝙰𝚂
+↓	
+𝚁𝙸
+↑	
+𝙰𝙿𝚂
+	
+BBBP↑ 	CARC↓	MUT↓	QED↑
+General-purpose LLMs
+Mistral (0-shot)	25.40	89.60	0.69	100.00	2.84	0.25	0.92	0.16	0.25	0.77
+Llama (0-shot)	20.40	98.60	0.72	100.00	2.86	0.20	0.90	0.18	0.24	0.79
+Claude-3.5 (0-shot)	30.00	96.00	0.64	100.00	2.66	0.26	0.91	0.16	0.22	0.77
+GPT-4o (0-shot)	19.60	90.60	0.72	100.00	2.66	0.19	0.90	0.18	0.21	0.77
+Mistral (1-shot)	63.80	99.60	0.60	93.10	2.61	0.31	0.90	0.16	0.20	0.78
+Llama (1-shot)	41.60	99.80	0.67	95.67	2.78	0.23	0.91	0.17	0.23	0.77
+Claude-3.5 (1-shot)	32.40	95.00	0.61	100.00	2.69	0.30	0.91	0.15	0.23	0.78
+GPT-4o (1-shot)	23.40	86.40	0.73	100.00	2.63	0.21	0.90	0.18	0.20	0.76
+Foundational LLMs for Chemistry
+
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	72.80	100.00	0.63	98.90	2.71	0.30	0.90	0.16	0.20	0.77
+
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+𝙻𝚕𝚊𝚖𝚊
+	18.20	87.00	0.67	98.90	2.90	0.27	0.90	0.14	0.23	0.76
+Generalist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	84.20	99.20	0.62	99.52	2.55	0.42	0.93	0.12	0.17	0.81
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+	80.00	91.20	0.57	99.00	2.49	0.44	0.93	0.12	0.17	0.82
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+	15.7	-0.8	-1.6	0.6	5.9	40.0	3.3	25.0	15.0	5.2
+• 
+
+The metrics, notations, and formatting have the same meanings as those in Table A3.
+
+Table A11:Overall Performance on 
+𝙱𝙳𝙴𝚀
+Model	
+𝚂𝚁
+↑	
+𝚅𝚊𝚕
+↑	
+𝚂𝚒𝚖
+↑	
+𝙽𝚘𝚟
+↑	
+𝚂𝙰𝚂
+↓	
+𝚁𝙸
+↑	
+𝙰𝙿𝚂
+	
+BBBP↑ 	DRD2↑	hERG↓	QED↑
+General-purpose LLMs
+Mistral (0-shot)	3.00	78.00	0.71	100.00	2.97	1.05	0.88	0.06	0.40	0.75
+Llama (0-shot)	2.20	96.00	0.68	100.00	3.46	0.60	0.96	0.07	0.48	0.78
+Claude-3.5 (0-shot)	4.80	96.60	0.62	100.00	2.76	0.57	0.92	0.04	0.52	0.79
+GPT-4o (0-shot)	3.40	87.60	0.71	100.00	2.75	0.42	0.93	0.07	0.55	0.82
+Mistral (1-shot)	21.60	99.80	0.58	84.26	3.11	1.16	0.91	0.15	0.49	0.77
+Llama (1-shot)	11.40	99.60	0.51	68.42	3.48	1.54	0.92	0.19	0.49	0.79
+Claude-3.5 (1-shot)	7.20	97.60	0.55	100.00	2.88	1.22	0.95	0.08	0.53	0.79
+GPT-4o (1-shot)	2.20	86.00	0.70	100.00	2.81	0.83	0.95	0.09	0.57	0.80
+Foundational LLMs for Chemistry
+
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	18.20	100.00	0.60	100.00	2.86	0.65	0.92	0.07	0.49	0.80
+
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+𝙻𝚕𝚊𝚖𝚊
+	3.00	87.40	0.68	100.00	3.13	1.64	0.94	0.08	0.49	0.79
+Generalist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	29.20	98.40	0.60	100.00	2.78	1.22	0.92	0.08	0.45	0.80
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+	28.40	92.20	0.58	100.00	2.75	0.88	0.92	0.07	0.47	0.80
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+	35.2	-1.4	3.4	18.7	10.6	5.2	1.1	-46.7	8.2	3.9
+• 
+
+The metrics, notations, and formatting have the same meanings as those in Table A3.
+
+Table A12:Overall Performance on 
+𝙷𝙻𝙼𝙿𝚀
+Model	
+𝚂𝚁
+↑	
+𝚅𝚊𝚕
+↑	
+𝚂𝚒𝚖
+↑	
+𝙽𝚘𝚟
+↑	
+𝚂𝙰𝚂
+↓	
+𝚁𝙸
+↑	
+𝙰𝙿𝚂
+		
+HIA↑ 	LIV↓	MUT↓	PlogP↑	QED↑
+General-purpose LLMs
+Mistral (0-shot)	11.60	82.40	0.79	100.00	2.91	1.76	0.99	0.38	0.20	0.51	0.77
+Llama (0-shot)	20.20	99.40	0.72	98.02	2.82	0.68	1.00	0.54	0.23	0.70	0.79
+Claude-3.5 (0-shot)	21.00	97.00	0.66	99.05	2.72	0.59	1.00	0.46	0.24	0.69	0.79
+GPT-4o (0-shot)	12.80	87.60	0.72	100.00	2.78	0.47	1.00	0.48	0.20	0.49	0.75
+Mistral (1-shot)	55.60	99.80	0.62	97.12	2.59	0.77	0.99	0.54	0.21	1.08	0.77
+Llama (1-shot)	28.00	99.60	0.70	97.86	2.72	0.75	1.00	0.56	0.24	0.83	0.78
+Claude-3.5 (1-shot)	25.00	95.00	0.61	97.60	2.60	0.72	1.00	0.53	0.25	0.89	0.78
+GPT-4o (1-shot)	13.40	87.40	0.71	100.00	2.82	0.65	1.00	0.50	0.21	0.61	0.73
+Foundational LLMs for Chemistry
+
+𝙻𝚕𝚊𝚂𝙼𝚘𝚕
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	37.80	100.00	0.68	100.00	2.66	0.66	1.00	0.58	0.22	0.92	0.73
+
+𝙲𝚑𝚎𝚖𝙳𝙵𝙼
+𝙻𝚕𝚊𝚖𝚊
+	10.80	90.60	0.68	98.15	3.01	1.04	0.98	0.43	0.19	0.68	0.77
+Generalist LLMs
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	74.60	99.80	0.61	99.46	2.49	1.36	1.00	0.53	0.18	1.43	0.79
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+⁢
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+	65.40	90.80	0.58	99.69	2.41	1.35	1.00	0.53	0.18	1.53	0.79
+
+𝙸𝚖𝚙𝚟
+⁢
+-
+⁢
+𝙶𝚎𝚗
+	34.2	0.0	-1.6	2.4	3.9	76.6	1.0	1.9	14.3	32.4	2.6
+• 
+
+The metrics, notations, and formatting have the same meanings as those in Table A3.
+
+G.3IND Evaluation with Unseen Instructions
+
+Table A13 presents the overall performance comparison of specialist and generalist 
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+s when evaluated with seen and unseen instructions.
+
+Table A13:Overall Performance with Unseen Instructions in IND Tasks
+Model	Instr	
+𝙱𝙿𝚀
+		
+𝙴𝙻𝚀
+		
+𝙰𝙲𝙴𝙿
+		
+𝙱𝙳𝙿𝚀
+		
+𝙳𝙷𝙼𝚀
+
+
+𝙶𝚎𝙻𝙻𝙼
+𝟺
+⁢
+𝙾
+⁢
+-
+⁢
+𝙲
+	
+𝚂𝚁
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑		
+𝚂𝚁
+↑	
+𝚂𝚒𝚖
+↑	
+𝚁𝙸
+↑
+Specialist LLMs
+
+-
+⁢
+𝙽
+𝙼𝚒����𝚝𝚛𝚊𝚕
+	seen	71.00	0.57	2.59		81.80	0.55	0.39		85.60	0.54	2.46		56.60	0.50	5.48		44.60	0.57	2.96
+unseen	68.60	0.55	2.33		84.60	0.53	0.41		86.80	0.53	2.28		59.40	0.47	5.79		49.40	0.56	3.19
+
+-
+⁢
+𝙽
+𝙻𝚕𝚊𝚖𝚊
+	seen	84.20	0.58	2.09		85.40	0.53	0.41		88.00	0.54	2.24		43.60	0.58	4.85		35.40	0.65	2.63
+unseen	74.20	0.57	2.02		88.60	0.54	0.42		87.00	0.52	2.14		37.00	0.59	5.27		37.60	0.64	2.77
+Generalist LLMs
+
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙼𝚒𝚜𝚝𝚛𝚊𝚕
+	seen	89.40	0.62	2.30		88.40	0.59	0.41		74.60	0.61	1.92		48.40	0.58	5.05		52.20	0.61	2.24
+unseen	89.60	0.62	2.01		87.60	0.60	0.37		78.00	0.63	1.75		46.60	0.60	4.57		50.20	0.61	2.79
+
+-
+⁢
+𝙿
+⁢
+(
+𝟷𝟶
+)
+𝙻𝚕𝚊𝚖𝚊
+	seen	79.40	0.57	2.67		79.00	0.56	0.41		72.60	0.57	2.27		42.60	0.55	5.89		41.80	0.57	3.32
+unseen	95.60	0.55	2.63		92.60	0.55	0.42		84.80	0.57	2.21		52.80	0.55	5.67		51.60	0.55	2.96
+• 
+
+‘Seen’ and ‘unseen’ indicate whether models are evaluated using instructions included during training or entirely novel instructions, respectively. ↑ and ↓ indicate whether higher or lower values of the corresponding metric are preferable. Within each row block, the best-performing model is highlighted in bold if the performance difference exceeds 5%.
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