chemutils.py

import rdkit
import rdkit.Chem as Chem
from scipy.sparse import csr_matrix
from scipy.sparse.csgraph import minimum_spanning_tree
from collections import defaultdict
from rdkit.Chem.EnumerateStereoisomers import EnumerateStereoisomers, StereoEnumerationOptions

MST_MAX_WEIGHT = 100 
MAX_NCAND = 2000

def set_atommap(mol, num=0):
    for atom in mol.GetAtoms():
        atom.SetAtomMapNum(num)

def get_mol(smiles):
    mol = Chem.MolFromSmiles(smiles)
    if mol is None: 
        return None
    Chem.Kekulize(mol)
    return mol

def get_smiles(mol):
    return Chem.MolToSmiles(mol, kekuleSmiles=True)

def decode_stereo(smiles2D):
    mol = Chem.MolFromSmiles(smiles2D)
    dec_isomers = list(EnumerateStereoisomers(mol))

    dec_isomers = [Chem.MolFromSmiles(Chem.MolToSmiles(mol, isomericSmiles=True)) for mol in dec_isomers]
    smiles3D = [Chem.MolToSmiles(mol, isomericSmiles=True) for mol in dec_isomers]

    chiralN = [atom.GetIdx() for atom in dec_isomers[0].GetAtoms() if int(atom.GetChiralTag()) > 0 and atom.GetSymbol() == "N"]
    if len(chiralN) > 0:
        for mol in dec_isomers:
            for idx in chiralN:
                mol.GetAtomWithIdx(idx).SetChiralTag(Chem.rdchem.ChiralType.CHI_UNSPECIFIED)
            smiles3D.append(Chem.MolToSmiles(mol, isomericSmiles=True))

    return smiles3D

def sanitize(mol):
    try:
        smiles = get_smiles(mol)
        mol = get_mol(smiles)
    except Exception as e:
        return None
    return mol

def copy_atom(atom):
    new_atom = Chem.Atom(atom.GetSymbol())
    new_atom.SetFormalCharge(atom.GetFormalCharge())
    new_atom.SetAtomMapNum(atom.GetAtomMapNum())
    return new_atom

def copy_edit_mol(mol):
    new_mol = Chem.RWMol(Chem.MolFromSmiles(''))
    for atom in mol.GetAtoms():
        new_atom = copy_atom(atom)
        new_mol.AddAtom(new_atom)
    for bond in mol.GetBonds():
        a1 = bond.GetBeginAtom().GetIdx()
        a2 = bond.GetEndAtom().GetIdx()
        bt = bond.GetBondType()
        new_mol.AddBond(a1, a2, bt)
    return new_mol

def get_clique_mol(mol, atoms):
    smiles = Chem.MolFragmentToSmiles(mol, atoms, kekuleSmiles=True)
    new_mol = Chem.MolFromSmiles(smiles, sanitize=False)
    new_mol = copy_edit_mol(new_mol).GetMol()
    new_mol = sanitize(new_mol) 
    return new_mol

def tree_decomp(mol):
    n_atoms = mol.GetNumAtoms()
    if n_atoms == 1:
        return [[0]], []

    cliques = []
    for bond in mol.GetBonds():
        a1 = bond.GetBeginAtom().GetIdx()
        a2 = bond.GetEndAtom().GetIdx()
        if not bond.IsInRing():
            cliques.append([a1,a2])

    ssr = [list(x) for x in Chem.GetSymmSSSR(mol)]
    cliques.extend(ssr)

    nei_list = [[] for i in range(n_atoms)]
    for i in range(len(cliques)):
        for atom in cliques[i]:
            nei_list[atom].append(i)
    
    
    for i in range(len(cliques)):
        if len(cliques[i]) <= 2: continue
        for atom in cliques[i]:
            for j in nei_list[atom]:
                if i >= j or len(cliques[j]) <= 2: continue
                inter = set(cliques[i]) & set(cliques[j])
                if len(inter) > 2:
                    cliques[i].extend(cliques[j])
                    cliques[i] = list(set(cliques[i]))
                    cliques[j] = []
    
    cliques = [c for c in cliques if len(c) > 0]
    nei_list = [[] for i in range(n_atoms)]
    for i in range(len(cliques)):
        for atom in cliques[i]:
            nei_list[atom].append(i)
    
    
    edges = defaultdict(int)
    for atom in range(n_atoms):
        if len(nei_list[atom]) <= 1: 
            continue
        cnei = nei_list[atom]
        bonds = [c for c in cnei if len(cliques[c]) == 2]
        rings = [c for c in cnei if len(cliques[c]) > 4]
        if len(bonds) > 2 or (len(bonds) == 2 and len(cnei) > 2): 
            cliques.append([atom])
            c2 = len(cliques) - 1
            for c1 in cnei:
                edges[(c1,c2)] = 1
        elif len(rings) > 2: 
            cliques.append([atom])
            c2 = len(cliques) - 1
            for c1 in cnei:
                edges[(c1,c2)] = MST_MAX_WEIGHT - 1
        else:
            for i in range(len(cnei)):
                for j in range(i + 1, len(cnei)):
                    c1,c2 = cnei[i],cnei[j]
                    inter = set(cliques[c1]) & set(cliques[c2])
                    if edges[(c1,c2)] < len(inter):
                        edges[(c1,c2)] = len(inter) 

    edges = [u + (MST_MAX_WEIGHT-v,) for u,v in edges.items()]
    if len(edges) == 0:
        return cliques, edges

    
    row,col,data = list(zip(*edges))
    n_clique = len(cliques)
    clique_graph = csr_matrix( (data,(row,col)), shape=(n_clique,n_clique) )
    junc_tree = minimum_spanning_tree(clique_graph)
    row,col = junc_tree.nonzero()
    edges = [(row[i],col[i]) for i in range(len(row))]
    return (cliques, edges)

def atom_equal(a1, a2):
    return a1.GetSymbol() == a2.GetSymbol() and a1.GetFormalCharge() == a2.GetFormalCharge()


def ring_bond_equal(b1, b2, reverse=False):
    b1 = (b1.GetBeginAtom(), b1.GetEndAtom())
    if reverse:
        b2 = (b2.GetEndAtom(), b2.GetBeginAtom())
    else:
        b2 = (b2.GetBeginAtom(), b2.GetEndAtom())
    return atom_equal(b1[0], b2[0]) and atom_equal(b1[1], b2[1])

def attach_mols_nx(ctr_mol, neighbors, prev_nodes, nei_amap):
    prev_nids = [node['nid'] for node in prev_nodes]
    for nei_node in prev_nodes + neighbors:
        nei_id, nei_mol = nei_node['nid'], nei_node['mol']
        amap = nei_amap[nei_id]
        for atom in nei_mol.GetAtoms():
            if atom.GetIdx() not in amap:
                new_atom = copy_atom(atom)
                amap[atom.GetIdx()] = ctr_mol.AddAtom(new_atom)

        if nei_mol.GetNumBonds() == 0:
            nei_atom = nei_mol.GetAtomWithIdx(0)
            ctr_atom = ctr_mol.GetAtomWithIdx(amap[0])
            ctr_atom.SetAtomMapNum(nei_atom.GetAtomMapNum())
        else:
            for bond in nei_mol.GetBonds():
                a1 = amap[bond.GetBeginAtom().GetIdx()]
                a2 = amap[bond.GetEndAtom().GetIdx()]
                if ctr_mol.GetBondBetweenAtoms(a1, a2) is None:
                    ctr_mol.AddBond(a1, a2, bond.GetBondType())
                elif nei_id in prev_nids: 
                    ctr_mol.RemoveBond(a1, a2)
                    ctr_mol.AddBond(a1, a2, bond.GetBondType())
    return ctr_mol

def local_attach_nx(ctr_mol, neighbors, prev_nodes, amap_list):
    ctr_mol = copy_edit_mol(ctr_mol)
    nei_amap = {nei['nid']: {} for nei in prev_nodes + neighbors}

    for nei_id,ctr_atom,nei_atom in amap_list:
        nei_amap[nei_id][nei_atom] = ctr_atom

    ctr_mol = attach_mols_nx(ctr_mol, neighbors, prev_nodes, nei_amap)
    return ctr_mol.GetMol()


def enum_attach_nx(ctr_mol, nei_node, amap, singletons):
    nei_mol,nei_idx = nei_node['mol'], nei_node['nid']
    att_confs = []
    black_list = [atom_idx for nei_id,atom_idx,_ in amap if nei_id in singletons]
    ctr_atoms = [atom for atom in ctr_mol.GetAtoms() if atom.GetIdx() not in black_list]
    ctr_bonds = [bond for bond in ctr_mol.GetBonds()]

    if nei_mol.GetNumBonds() == 0: 
        nei_atom = nei_mol.GetAtomWithIdx(0)
        used_list = [atom_idx for _,atom_idx,_ in amap]
        for atom in ctr_atoms:
            if atom_equal(atom, nei_atom) and atom.GetIdx() not in used_list:
                new_amap = amap + [(nei_idx, atom.GetIdx(), 0)]
                att_confs.append( new_amap )
   
    elif nei_mol.GetNumBonds() == 1: 
        bond = nei_mol.GetBondWithIdx(0)
        bond_val = int(bond.GetBondTypeAsDouble())
        b1,b2 = bond.GetBeginAtom(), bond.GetEndAtom()

        for atom in ctr_atoms: 
            
            if atom.GetAtomicNum() == 6 and atom.GetTotalNumHs() < bond_val:
                continue
            if atom_equal(atom, b1):
                new_amap = amap + [(nei_idx, atom.GetIdx(), b1.GetIdx())]
                att_confs.append( new_amap )
            elif atom_equal(atom, b2):
                new_amap = amap + [(nei_idx, atom.GetIdx(), b2.GetIdx())]
                att_confs.append( new_amap )
    else: 
        
        for a1 in ctr_atoms:
            for a2 in nei_mol.GetAtoms():
                if atom_equal(a1, a2):
                    
                    if a1.GetAtomicNum() == 6 and a1.GetTotalNumHs() + a2.GetTotalNumHs() < 4:
                        continue
                    new_amap = amap + [(nei_idx, a1.GetIdx(), a2.GetIdx())]
                    att_confs.append( new_amap )

        
        if ctr_mol.GetNumBonds() > 1:
            for b1 in ctr_bonds:
                for b2 in nei_mol.GetBonds():
                    if ring_bond_equal(b1, b2):
                        new_amap = amap + [(nei_idx, b1.GetBeginAtom().GetIdx(), b2.GetBeginAtom().GetIdx()), (nei_idx, b1.GetEndAtom().GetIdx(), b2.GetEndAtom().GetIdx())]
                        att_confs.append( new_amap )

                    if ring_bond_equal(b1, b2, reverse=True):
                        new_amap = amap + [(nei_idx, b1.GetBeginAtom().GetIdx(), b2.GetEndAtom().GetIdx()), (nei_idx, b1.GetEndAtom().GetIdx(), b2.GetBeginAtom().GetIdx())]
                        att_confs.append( new_amap )
    return att_confs


def enum_assemble_nx(node, neighbors, prev_nodes=[], prev_amap=[]):
    all_attach_confs = []
    singletons = [nei_node['nid'] for nei_node in neighbors + prev_nodes if nei_node['mol'].GetNumAtoms() == 1]

    def search(cur_amap, depth):
        if len(all_attach_confs) > MAX_NCAND:
            return
        if depth == len(neighbors):
            all_attach_confs.append(cur_amap)
            return

        nei_node = neighbors[depth]
        cand_amap = enum_attach_nx(node['mol'], nei_node, cur_amap, singletons)
        cand_smiles = set()
        candidates = []
        for amap in cand_amap:
            cand_mol = local_attach_nx(node['mol'], neighbors[:depth+1], prev_nodes, amap)
            cand_mol = sanitize(cand_mol)
            if cand_mol is None:
                continue
            smiles = get_smiles(cand_mol)
            if smiles in cand_smiles:
                continue
            cand_smiles.add(smiles)
            candidates.append(amap)

        if len(candidates) == 0:
            return []

        for new_amap in candidates:
            search(new_amap, depth + 1)

    search(prev_amap, 0)
    cand_smiles = set()
    candidates = []
    for amap in all_attach_confs:
        cand_mol = local_attach_nx(node['mol'], neighbors, prev_nodes, amap)
        cand_mol = Chem.MolFromSmiles(Chem.MolToSmiles(cand_mol))
        smiles = Chem.MolToSmiles(cand_mol)
        if smiles in cand_smiles:
            continue
        cand_smiles.add(smiles)
        Chem.Kekulize(cand_mol)
        candidates.append( (smiles,cand_mol,amap) )

    return candidates


def dfs_assemble_nx(graph, cur_mol, global_amap, fa_amap, cur_node_id, fa_node_id):
    cur_node = graph.nodes_dict[cur_node_id]
    fa_node = graph.nodes_dict[fa_node_id] if fa_node_id is not None else None

    fa_nid = fa_node['nid'] if fa_node is not None else -1
    prev_nodes = [fa_node] if fa_node is not None else []

    children_id = [nei for nei in graph[cur_node_id] if graph.nodes_dict[nei]['nid'] != fa_nid]
    children = [graph.nodes_dict[nei] for nei in children_id]
    neighbors = [nei for nei in children if nei['mol'].GetNumAtoms() > 1]
    neighbors = sorted(neighbors, key=lambda x:x['mol'].GetNumAtoms(), reverse=True)
    singletons = [nei for nei in children if nei['mol'].GetNumAtoms() == 1]
    neighbors = singletons + neighbors

    cur_amap = [(fa_nid,a2,a1) for nid,a1,a2 in fa_amap if nid == cur_node['nid']]
    cands = enum_assemble_nx(graph.nodes_dict[cur_node_id], neighbors, prev_nodes, cur_amap)
    if len(cands) == 0:
        return

    cand_smiles, _, cand_amap = zip(*cands)
    label_idx = cand_smiles.index(cur_node['label'])
    label_amap = cand_amap[label_idx]

    for nei_id,ctr_atom,nei_atom in label_amap:
        if nei_id == fa_nid:
            continue
        global_amap[nei_id][nei_atom] = global_amap[cur_node['nid']][ctr_atom]
    
    cur_mol = attach_mols_nx(cur_mol, children, [], global_amap) 
    for nei_node_id, nei_node in zip(children_id, children):
        if not nei_node['is_leaf']:
            dfs_assemble_nx(graph, cur_mol, global_amap, label_amap, nei_node_id, cur_node_id)