portable_rdock_pipeline/libs/adaptive/features.py

from __future__ import annotations

from dataclasses import dataclass
from typing import Dict, Iterable, List, Tuple

import numpy as np
import pandas as pd
from rdkit import Chem
from rdkit.Chem import AllChem, Descriptors, Lipinski, MolSurf, rdMolDescriptors
from rdkit.Chem.Scaffolds import MurckoScaffold
from rdkit.DataStructs import TanimotoSimilarity

try:
    from rdkit.Chem import rdFreeSASA
except Exception:  # pragma: no cover
    rdFreeSASA = None  # type: ignore[assignment]


@dataclass
class FeatureValue:
    value: float | None
    available: bool
    source: str
    feature_type: str


@dataclass
class FeatureBundle:
    object_id: str
    features: Dict[str, FeatureValue]

    def to_records(self, channel: str, round_idx: int | None = None) -> List[dict]:
        rows: List[dict] = []
        for name, fv in sorted(self.features.items()):
            rows.append(
                {
                    "object_id": self.object_id,
                    "round": round_idx,
                    "channel": channel,
                    "feature_name": name,
                    "value": fv.value,
                    "available": bool(fv.available),
                    "source": fv.source,
                    "feature_type": fv.feature_type,
                }
            )
        return rows


def _fv(value: float | None, available: bool, source: str, feature_type: str) -> FeatureValue:
    return FeatureValue(value=value, available=available, source=source, feature_type=feature_type)


def _safe_float(value: float | int | None) -> float | None:
    if value is None:
        return None
    try:
        v = float(value)
    except Exception:
        return None
    if not np.isfinite(v):
        return None
    return v


def _compute_ligand_sasa(mol: Chem.Mol) -> Tuple[float | None, bool]:
    if rdFreeSASA is None:
        return None, False
    try:
        if mol.GetNumConformers() == 0:
            m = Chem.AddHs(Chem.Mol(mol))
            status = AllChem.EmbedMolecule(m, AllChem.ETKDGv3())
            if int(status) != 0:
                return None, False
        else:
            m = Chem.Mol(mol)

        if m.GetNumConformers() == 0:
            return None, False

        radii = rdFreeSASA.classifyAtoms(m)
        sasa = rdFreeSASA.CalcSASA(m, radii)
        return _safe_float(sasa), True
    except Exception:
        return None, False


def build_ligand_feature_bundle(
    ligand_id: str,
    smiles: str,
    fingerprint: np.ndarray,
    reference_mol: Chem.Mol | None = None,
    compute_partial_charges: bool = True,
    compute_sasa: bool = True,
) -> FeatureBundle:
    mol = Chem.MolFromSmiles(smiles)
    if mol is None:
        raise ValueError(f"Invalid SMILES for ligand {ligand_id}: {smiles}")

    m_h = Chem.AddHs(Chem.Mol(mol))
    if compute_partial_charges:
        try:
            AllChem.ComputeGasteigerCharges(m_h)
            partial_charges = []
            for atom in m_h.GetAtoms():
                prop = atom.GetProp("_GasteigerCharge") if atom.HasProp("_GasteigerCharge") else "nan"
                try:
                    q = float(prop)
                except Exception:
                    continue
                if np.isfinite(q):
                    partial_charges.append(q)
            if partial_charges:
                mean_abs_q = float(np.mean(np.abs(partial_charges)))
                total_q = float(np.sum(partial_charges))
                has_q = True
            else:
                mean_abs_q = None
                total_q = None
                has_q = False
        except Exception:
            mean_abs_q = None
            total_q = None
            has_q = False
    else:
        mean_abs_q = None
        total_q = None
        has_q = False

    aromatic_rings = rdMolDescriptors.CalcNumAromaticRings(mol)
    formal_charge = Chem.GetFormalCharge(mol)
    heavy_atoms = mol.GetNumHeavyAtoms()
    frac_csp3 = rdMolDescriptors.CalcFractionCSP3(mol)
    bertz_ct = Descriptors.BertzCT(mol)
    balaban_j = Descriptors.BalabanJ(mol)
    topological_complexity = rdMolDescriptors.CalcChi0v(mol)

    if compute_sasa:
        ligand_sasa, has_sasa = _compute_ligand_sasa(m_h)
    else:
        ligand_sasa, has_sasa = None, False

    reference_similarity = None
    scaffold_match = None
    chemical_distance = None
    if reference_mol is not None:
        fp_gen = AllChem.GetMorganGenerator(radius=2, fpSize=int(fingerprint.shape[0]))
        ref_fp = fp_gen.GetFingerprint(reference_mol)
        lig_fp = fp_gen.GetFingerprint(mol)
        sim = TanimotoSimilarity(ref_fp, lig_fp)
        reference_similarity = float(sim)
        chemical_distance = float(1.0 - sim)

        ref_scaffold = MurckoScaffold.MurckoScaffoldSmiles(mol=reference_mol)
        lig_scaffold = MurckoScaffold.MurckoScaffoldSmiles(mol=mol)
        scaffold_match = float(ref_scaffold == lig_scaffold)

    features: Dict[str, FeatureValue] = {
        "ligand_mw": _fv(_safe_float(Descriptors.MolWt(mol)), True, "rdkit", "exact"),
        "ligand_logp": _fv(_safe_float(Descriptors.MolLogP(mol)), True, "rdkit", "exact"),
        "ligand_tpsa": _fv(_safe_float(MolSurf.TPSA(mol)), True, "rdkit", "exact"),
        "ligand_hbd": _fv(_safe_float(Lipinski.NumHDonors(mol)), True, "rdkit", "exact"),
        "ligand_hba": _fv(_safe_float(Lipinski.NumHAcceptors(mol)), True, "rdkit", "exact"),
        "ligand_rotatable_bonds": _fv(_safe_float(Lipinski.NumRotatableBonds(mol)), True, "rdkit", "exact"),
        "ligand_aromatic_ring_count": _fv(_safe_float(aromatic_rings), True, "rdkit", "exact"),
        "ligand_formal_charge": _fv(_safe_float(formal_charge), True, "rdkit", "exact"),
        "ligand_partial_charge_abs_mean": _fv(mean_abs_q, has_q, "rdkit", "approximate"),
        "ligand_partial_charge_total": _fv(total_q, has_q, "rdkit", "approximate"),
        "ligand_topological_bertz": _fv(_safe_float(bertz_ct), True, "rdkit", "exact"),
        "ligand_topological_balaban_j": _fv(_safe_float(balaban_j), True, "rdkit", "exact"),
        "ligand_topological_chi0v": _fv(_safe_float(topological_complexity), True, "rdkit", "exact"),
        "ligand_fraction_csp3": _fv(_safe_float(frac_csp3), True, "rdkit", "exact"),
        "ligand_heavy_atom_count": _fv(_safe_float(heavy_atoms), True, "rdkit", "exact"),
        "ligand_sasa": _fv(ligand_sasa, has_sasa, "geometric", "approximate"),
        "similarity_to_reference": _fv(reference_similarity, reference_similarity is not None, "rdkit", "exact"),
        "scaffold_match": _fv(scaffold_match, scaffold_match is not None, "rdkit", "exact"),
        "chemical_distance_to_reference": _fv(chemical_distance, chemical_distance is not None, "rdkit", "exact"),
    }

    for i, bit in enumerate(fingerprint.astype(float).tolist()):
        features[f"morgan_fp_{i:04d}"] = _fv(float(bit), True, "rdkit", "exact")

    return FeatureBundle(object_id=ligand_id, features=features)


def build_protein_feature_bundle(target_id: str, sequence_features: Dict[str, float], structure_features: Dict[str, float]) -> FeatureBundle:
    seq_len = float(sequence_features.get("seq_length", 1.0) or 1.0)
    hydrophobic = sum(sequence_features.get(f"aa_frac_{aa}", 0.0) for aa in ["A", "V", "I", "L", "M", "F", "W", "Y"])
    charged = sum(sequence_features.get(f"aa_frac_{aa}", 0.0) for aa in ["K", "R", "H", "D", "E"])
    polar = sum(sequence_features.get(f"aa_frac_{aa}", 0.0) for aa in ["S", "T", "N", "Q", "C"])

    residue_count = float(structure_features.get("residue_count", 0.0))
    mean_extent = float(structure_features.get("mean_spatial_extent", 0.0))
    pocket_residues = float(structure_features.get("pocket_residue_count", 0.0))

    approx_volume = float(max(0.0, mean_extent**3))
    pocket_coverage = float(pocket_residues / max(residue_count, 1.0))

    features = {
        "pocket_hydrophobic_fraction": _fv(hydrophobic, True, "protein", "exact"),
        "pocket_charged_fraction": _fv(charged, True, "protein", "exact"),
        "pocket_polar_fraction": _fv(polar, True, "protein", "exact"),
        "pocket_residue_count": _fv(residue_count, True, "protein", "exact"),
        "pocket_volume_approx": _fv(approx_volume, True, "geometric", "approximate"),
        "pocket_coverage_fraction": _fv(pocket_coverage, True, "geometric", "approximate"),
        "pocket_sequence_length": _fv(seq_len, True, "protein", "exact"),
    }
    return FeatureBundle(object_id=target_id, features=features)


def build_complex_feature_bundle(
    ligand_id: str,
    docking_score: float,
    interface_features: Dict[str, float],
    ligand_bundle: FeatureBundle,
    protein_bundle: FeatureBundle,
) -> FeatureBundle:
    lig = ligand_bundle.features
    prot = protein_bundle.features

    logp = lig.get("ligand_logp", _fv(None, False, "rdkit", "exact")).value or 0.0
    tpsa = lig.get("ligand_tpsa", _fv(None, False, "rdkit", "exact")).value or 0.0
    charge_mag = lig.get("ligand_partial_charge_abs_mean", _fv(None, False, "rdkit", "approximate")).value
    heavy_atoms = lig.get("ligand_heavy_atom_count", _fv(None, False, "rdkit", "exact")).value or 1.0
    pocket_volume = prot.get("pocket_volume_approx", _fv(None, False, "geometric", "approximate")).value or 1.0
    pocket_hydrophobic = prot.get("pocket_hydrophobic_fraction", _fv(None, False, "protein", "exact")).value or 0.0

    interface_contact_proxy = float(interface_features.get("interface_contact_proxy", max(0.0, -docking_score / 8.0)))
    hbond_proxy = float(interface_features.get("hbond_proxy", max(0.0, tpsa / 100.0)))
    shape_proxy = float(interface_features.get("shape_proxy", max(0.0, 1.0 / (1.0 + abs(docking_score)))))

    contact_count = max(1.0, heavy_atoms * (0.3 + interface_contact_proxy))
    polar_contacts = contact_count * min(1.0, tpsa / 120.0)
    hydrophobic_contacts = contact_count * min(1.0, max(0.0, logp) / 6.0) * (0.5 + pocket_hydrophobic)
    clash_count = max(0.0, docking_score - 9.0)
    min_distance = max(1.5, 6.0 - interface_contact_proxy)
    pocket_coverage = min(1.0, contact_count / max(10.0, pocket_volume / 20.0))
    interaction_density = contact_count / max(1.0, pocket_volume)

    ligand_sasa = lig.get("ligand_sasa", _fv(None, False, "geometric", "approximate")).value
    protein_sasa = pocket_volume * 0.75
    if ligand_sasa is not None:
        complex_sasa = max(1.0, protein_sasa + ligand_sasa - 0.5 * contact_count)
        buried_sasa = max(0.0, protein_sasa + ligand_sasa - complex_sasa)
        burial_ratio = buried_sasa / max(ligand_sasa, 1e-6)
        sasa_available = True
    else:
        complex_sasa = None
        buried_sasa = None
        burial_ratio = None
        sasa_available = False

    if charge_mag is not None:
        electrostatic_proxy = -charge_mag * max(0.5, 5.0 - min_distance)
        electro_available = True
    else:
        electrostatic_proxy = None
        electro_available = False

    contact_energy = -0.15 * contact_count
    steric_penalty = 0.6 * clash_count
    hydrophobic_proxy = -0.1 * hydrophobic_contacts
    interaction_decomp = contact_energy + hydrophobic_proxy + (electrostatic_proxy or 0.0) + steric_penalty

    features = {
        "complex_contact_count": _fv(float(contact_count), True, "interaction", "proxy"),
        "complex_hbond_proxy": _fv(float(hbond_proxy), True, "interaction", "proxy"),
        "complex_polar_contact_count": _fv(float(polar_contacts), True, "interaction", "proxy"),
        "complex_hydrophobic_contact_proxy": _fv(float(hydrophobic_contacts), True, "interaction", "proxy"),
        "complex_clash_count": _fv(float(clash_count), True, "interaction", "proxy"),
        "complex_min_distance": _fv(float(min_distance), True, "geometric", "approximate"),
        "complex_pocket_coverage": _fv(float(pocket_coverage), True, "interaction", "proxy"),
        "complex_interaction_density": _fv(float(interaction_density), True, "interaction", "proxy"),
        "complex_ligand_sasa": _fv(_safe_float(ligand_sasa), ligand_sasa is not None, "geometric", "approximate"),
        "complex_protein_sasa": _fv(_safe_float(protein_sasa), True, "geometric", "approximate"),
        "complex_sasa": _fv(_safe_float(complex_sasa), sasa_available, "geometric", "approximate"),
        "complex_buried_sasa": _fv(_safe_float(buried_sasa), sasa_available, "geometric", "approximate"),
        "complex_shape_complementarity": _fv(float(shape_proxy), True, "geometric", "proxy"),
        "complex_ligand_burial_ratio": _fv(_safe_float(burial_ratio), sasa_available, "geometric", "approximate"),
        "energy_contact_proxy": _fv(float(contact_energy), True, "energy_proxy", "proxy"),
        "energy_electrostatic_proxy": _fv(_safe_float(electrostatic_proxy), electro_available, "energy_proxy", "proxy"),
        "energy_steric_clash_penalty": _fv(float(steric_penalty), True, "energy_proxy", "proxy"),
        "energy_hydrophobic_proxy": _fv(float(hydrophobic_proxy), True, "energy_proxy", "proxy"),
        "energy_interaction_decomposition": _fv(float(interaction_decomp), True, "energy_proxy", "proxy"),
    }

    return FeatureBundle(object_id=ligand_id, features=features)


def build_rdock_feature_bundle(
    ligand_id: str,
    parsed_row: Dict[str, float | int | str | bool | None],
) -> FeatureBundle:
    """Build a feature bundle from rDock-native and rDock-derived per-ligand outputs."""

    def _as_feature(
        key: str,
        source: str,
        ftype: str,
    ) -> FeatureValue:
        value = _safe_float(parsed_row.get(key))  # type: ignore[arg-type]
        return _fv(value, value is not None, source, ftype if value is not None else "unavailable")

    features: Dict[str, FeatureValue] = {
        "rdock_total_score": _as_feature("rdock_total_score", "rdock_native", "exact"),
        "rdock_pose_rank": _as_feature("rdock_pose_rank", "rdock_native", "exact"),
        "n_generated_poses": _as_feature("n_generated_poses", "rdock_native", "exact"),
        "best_pose_score": _as_feature("best_pose_score", "rdock_native", "exact"),
        "mean_top3_pose_score": _as_feature("mean_top3_pose_score", "rdock_native", "exact"),
        "mean_top5_pose_score": _as_feature("mean_top5_pose_score", "rdock_native", "exact"),
        "std_top5_pose_score": _as_feature("std_top5_pose_score", "rdock_native", "exact"),
        "pose_score_gap_1_2": _as_feature("pose_score_gap_1_2", "rdock_native", "exact"),
        "rdock_restraint_term": _as_feature("rdock_restraint_term", "rdock_native", "exact"),
        "rdock_internal_ligand_term": _as_feature("rdock_internal_ligand_term", "rdock_native", "exact"),
        "rdock_polar_term": _as_feature("rdock_polar_term", "rdock_native", "exact"),
        "rdock_vdw_term": _as_feature("rdock_vdw_term", "rdock_native", "exact"),
        "top_pose_rmsd_consistency": _as_feature("top_pose_rmsd_consistency", "rdock_derived", "proxy"),
        "contact_overlap_consistency": _as_feature("contact_overlap_consistency", "rdock_derived", "proxy"),
        "hotspot_contact_frequency": _as_feature("hotspot_contact_frequency", "rdock_derived", "proxy"),
        "subpocket_match_score": _as_feature("subpocket_match_score", "rdock_derived", "proxy"),
        "replicate_mean_score": _as_feature("replicate_mean_score", "rdock_derived", "proxy"),
        "replicate_score_variance": _as_feature("replicate_score_variance", "rdock_derived", "proxy"),
        "replicate_consensus_score": _as_feature("replicate_consensus_score", "rdock_derived", "proxy"),
    }
    return FeatureBundle(object_id=ligand_id, features=features)


def merge_bundles(object_id: str, bundles: Iterable[FeatureBundle]) -> FeatureBundle:
    merged: Dict[str, FeatureValue] = {}
    for bundle in bundles:
        merged.update(bundle.features)
    return FeatureBundle(object_id=object_id, features=merged)


def bundles_to_wide_frames(
    bundles: List[FeatureBundle],
    ordered_feature_names: List[str] | None = None,
) -> Tuple[pd.DataFrame, pd.DataFrame, List[str]]:
    if not bundles:
        return pd.DataFrame(), pd.DataFrame(), []

    if ordered_feature_names is None:
        feature_set = set()
        for bundle in bundles:
            feature_set.update(bundle.features.keys())
        ordered_feature_names = sorted(feature_set)

    value_rows = []
    mask_rows = []
    for bundle in bundles:
        vrow = {"ligand_id": bundle.object_id}
        mrow = {"ligand_id": bundle.object_id}
        for name in ordered_feature_names:
            fv = bundle.features.get(name)
            if fv is None or not fv.available or fv.value is None:
                vrow[name] = np.nan
                mrow[f"mask_{name}"] = 0
            else:
                vrow[name] = float(fv.value)
                mrow[f"mask_{name}"] = 1
        value_rows.append(vrow)
        mask_rows.append(mrow)

    return pd.DataFrame(value_rows), pd.DataFrame(mask_rows), ordered_feature_names


def compute_feature_diagnostics(values_df: pd.DataFrame, masks_df: pd.DataFrame, target: pd.Series | None = None) -> pd.DataFrame:
    if values_df.empty:
        return pd.DataFrame(columns=["feature", "missing_frac", "mean", "std", "min", "max", "is_constant", "corr_to_target"])

    numeric_cols = [c for c in values_df.columns if c != "ligand_id"]
    rows = []
    for col in numeric_cols:
        vals = pd.to_numeric(values_df[col], errors="coerce")
        mask_col = f"mask_{col}"
        if mask_col in masks_df.columns:
            missing_frac = 1.0 - float(pd.to_numeric(masks_df[mask_col], errors="coerce").mean())
        else:
            missing_frac = float(vals.isna().mean())

        finite_vals = vals[np.isfinite(vals)]
        is_constant = finite_vals.nunique(dropna=True) <= 1 if not finite_vals.empty else True

        if target is not None and len(target) == len(vals):
            target_num = pd.to_numeric(target, errors="coerce")
            paired = pd.concat([vals, target_num], axis=1).dropna()
            if paired.shape[0] >= 3 and paired.iloc[:, 0].nunique(dropna=True) > 1 and paired.iloc[:, 1].nunique(dropna=True) > 1:
                corr = paired.iloc[:, 0].corr(paired.iloc[:, 1])
                corr_val = float(corr) if corr is not None and np.isfinite(corr) else np.nan
            else:
                corr_val = np.nan
        else:
            corr_val = np.nan

        rows.append(
            {
                "feature": col,
                "missing_frac": float(missing_frac),
                "mean": float(finite_vals.mean()) if not finite_vals.empty else np.nan,
                "std": float(finite_vals.std()) if not finite_vals.empty else np.nan,
                "min": float(finite_vals.min()) if not finite_vals.empty else np.nan,
                "max": float(finite_vals.max()) if not finite_vals.empty else np.nan,
                "is_constant": bool(is_constant),
                "corr_to_target": corr_val,
            }
        )

    return pd.DataFrame(rows).sort_values(["missing_frac", "feature"], ascending=[False, True]).reset_index(drop=True)