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Development of Robust Quantitative Structure-Activity Relationship Models for CYP2C9, CYP2D6, and CYP3A4 Catalysis and Inhibition Eric Gonzalez1, Sankalp Jain1, Pranav Shah1, Nao Torimoto-Katori, Alexey Zakharov, Ð/C19/C21ac-Trung Nguy~^en, Srilatha Sakamuru, Ruili Huang, Menghang Xia, R. Scott Obach, Cornelis E. C. A.... | 822.full_5.pdf |
efficacy of a compound when the increased expression and activity leads to rapid clearance. To address these concerns, compounds are sought that possess a well distributed metabolism pro file across multiple enzymes and clearance mechanisms (Zientek and Youdim, 2015). The current standard for preliminary estimation of th... | 822.full_5.pdf |
a View Lux plate reader (Perkin Elmer, Shelton, CT). Data were expressed as rel-ative luminescence units. The concentration-response activity data for each compound, relative to con-trol, was fit with the four-parameter Hill equation to obtain percent activity and potency values. The complete P450-Glo q HTS data sets ha... | 822.full_5.pdf |
descriptors (0 throughout) and descriptors with low variance ( <0. 4) were removed. For the final modeling exercise, we used 1164 descriptors. Machine Learning Methods —Strati fied Bagging with Random Forest and Multi-Task Deep Neural Networks. Random forest (with default param-eters) was used as a base classi fier (Brei... | 822.full_5.pdf |
distributions between substrates of the enzymes except for CYP2D6 substrates, which displayed lower molecular weight and lower TPSAcompared with CYP2C9 and CYP3A4 (Fig. 2). Furthermore, a directcorrelation between the calculated t 1/2values and the abovementioned molecular descriptors was not apparent. Additionally, we... | 822.full_5.pdf |
enzyme, the reported metabolism of this archaic compound is limited (Chaudhuri et al., 1976; Yeh, 1991) and is solely categorized as an inhibitor of CYP2D6 in the Drug Interactions Flockhart Table (https://drug-interactions. medicine. iu. edu/Main Table. aspx), illustrating the pres-ence of missing substrate/inhibitor ... | 822.full_5.pdf |
for all six data sets (three substrate 1three inhibitor) showed BACC values close to or above 70%. For the CYP3A4 substrate data set, a DNN-based model with dragon descriptors performed the best (BACC = 76%; MCC = 0. 51), closely followed by SB with a com-bination of Morgan fingerprints and five physicochemical propertie... | 822.full_5.pdf |
which will not only help advance drug design efforts but also provide a better understanding of the structure-activity relationship for major cyto-chrome P450 enzymes. The bene fits gained by the scienti fic community from this effort include 1) enhancing lead optimization by guiding struc-ture modifi cation, 2) improving... | 822.full_5.pdf |
multiple ligands simultaneously. The issue of cytochrome P450 cooper-ativity and allosteric interactions have since been reviewed extensively (Davydov and Halpert, 2008; Denisov et al., 2009). However, it is still necessary to evaluate the cytochrome P450-ligand binding empirically, as predictive models do not exist fo... | 822.full_5.pdf |
P450 enzymes that catalyze the metabolism of new chemical entities is essential at the preclinical phase of the drug discovery and developmentprocess. For more than 20 years, health authorities have provided guid-ance toward the characterization of in vitro drug interactions involving cytochromes P450, as well as other... | 822.full_5.pdf |
Berthold MR, Cebron N, Dill F, Gabriel TR, Kotter T, Meinl T, Ohl P, Sieb C, Thiel K, and Wis-wedel B (2008) KNIME: the Konstanz information miner, in Data Analysis, Machine Learning and Applications (Burkhardt H, Schmidt-Thieme L, Decker R, eds) pp 319-326, Springer Berlin Heidelberg. Boulenc X, Nicolas O, Hermabessie... | 822.full_5.pdf |
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