fast_jtnn/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
from vocab import Vocab

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, clearAromaticFlags=True)
    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) #We assume this is not None
    return new_mol

def tree_decomp(mol):
    n_atoms = mol.GetNumAtoms()
    if n_atoms == 1: #special case
        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)
    
    #Merge Rings with intersection > 2 atoms
    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)
    
    #Build edges and add singleton cliques
    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): #In general, if len(cnei) >= 3, a singleton should be added, but 1 bond + 2 ring is currently not dealt with.
            cliques.append([atom])
            c2 = len(cliques) - 1
            for c1 in cnei:
                edges[(c1,c2)] = 1
        elif len(rings) > 2: #Multiple (n>2) complex rings
            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) #cnei[i] < cnei[j] by construction

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

    #Compute Maximum Spanning Tree
    row,col,data = 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()

#Bond type not considered because all aromatic (so SINGLE matches DOUBLE)
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(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: #father node overrides
                    ctr_mol.RemoveBond(a1, a2)
                    ctr_mol.AddBond(a1, a2, bond.GetBondType())
    return ctr_mol

def local_attach(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(ctr_mol, neighbors, prev_nodes, nei_amap)
    return ctr_mol.GetMol()

#This version records idx mapping between ctr_mol and nei_mol
def enum_attach(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: #neighbor singleton
        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: #neighbor is a bond
        bond = nei_mol.GetBondWithIdx(0)
        bond_val = int(bond.GetBondTypeAsDouble())
        b1,b2 = bond.GetBeginAtom(), bond.GetEndAtom()

        for atom in ctr_atoms: 
            #Optimize if atom is carbon (other atoms may change valence)
            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: 
        #intersection is an atom
        for a1 in ctr_atoms:
            for a2 in nei_mol.GetAtoms():
                if atom_equal(a1, a2):
                    #Optimize if atom is carbon (other atoms may change valence)
                    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 )

        #intersection is an bond
        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

#Try rings first: Speed-Up 
def enum_assemble(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(node.mol, nei_node, cur_amap, singletons)
        cand_smiles = set()
        candidates = []
        for amap in cand_amap:
            cand_mol = local_attach(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 = []
    aroma_score = []
    for amap in all_attach_confs:
        cand_mol = local_attach(node.mol, neighbors, prev_nodes, amap)
        cand_mol = Chem.MolFromSmiles(Chem.MolToSmiles(cand_mol))
        smiles = Chem.MolToSmiles(cand_mol)
        if smiles in cand_smiles or check_singleton(cand_mol, node, neighbors) == False:
            continue
        cand_smiles.add(smiles)
        candidates.append( (smiles,amap) )
        aroma_score.append( check_aroma(cand_mol, node, neighbors) )

    return candidates, aroma_score 

def check_singleton(cand_mol, ctr_node, nei_nodes):
    rings = [node for node in nei_nodes + [ctr_node] if node.mol.GetNumAtoms() > 2]
    singletons = [node for node in nei_nodes + [ctr_node] if node.mol.GetNumAtoms() == 1]
    if len(singletons) > 0 or len(rings) == 0: return True

    n_leaf2_atoms = 0
    for atom in cand_mol.GetAtoms():
        nei_leaf_atoms = [a for a in atom.GetNeighbors() if not a.IsInRing()] #a.GetDegree() == 1]
        if len(nei_leaf_atoms) > 1: 
            n_leaf2_atoms += 1

    return n_leaf2_atoms == 0

def check_aroma(cand_mol, ctr_node, nei_nodes):
    rings = [node for node in nei_nodes + [ctr_node] if node.mol.GetNumAtoms() >= 3]
    if len(rings) < 2: return 0 #Only multi-ring system needs to be checked

    get_nid = lambda x: 0 if x.is_leaf else x.nid
    benzynes = [get_nid(node) for node in nei_nodes + [ctr_node] if node.smiles in Vocab.benzynes] 
    penzynes = [get_nid(node) for node in nei_nodes + [ctr_node] if node.smiles in Vocab.penzynes] 
    if len(benzynes) + len(penzynes) == 0: 
        return 0 #No specific aromatic rings

    n_aroma_atoms = 0
    for atom in cand_mol.GetAtoms():
        if atom.GetAtomMapNum() in benzynes+penzynes and atom.GetIsAromatic():
            n_aroma_atoms += 1

    if n_aroma_atoms >= len(benzynes) * 4 + len(penzynes) * 3:
        return 1000
    else:
        return -0.001 

#Only used for debugging purpose
def dfs_assemble(cur_mol, global_amap, fa_amap, cur_node, fa_node):
    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 = [nei for nei in cur_node.neighbors if nei.nid != fa_nid]
    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(cur_node, neighbors, prev_nodes, cur_amap)

    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(cur_mol, children, [], global_amap) #father is already attached
    for nei_node in children:
        if not nei_node.is_leaf:
            dfs_assemble(cur_mol, global_amap, label_amap, nei_node, cur_node)

if __name__ == "__main__":
    import sys
    from mol_tree import MolTree
    lg = rdkit.RDLogger.logger() 
    lg.setLevel(rdkit.RDLogger.CRITICAL)
    
    smiles = ["O=C1[C@@H]2C=C[C@@H](C=CC2)C1(c1ccccc1)c1ccccc1","O=C([O-])CC[C@@]12CCCC[C@]1(O)OC(=O)CC2", "ON=C1C[C@H]2CC3(C[C@@H](C1)c1ccccc12)OCCO3", "C[C@H]1CC(=O)[C@H]2[C@@]3(O)C(=O)c4cccc(O)c4[C@@H]4O[C@@]43[C@@H](O)C[C@]2(O)C1", 'Cc1cc(NC(=O)CSc2nnc3c4ccccc4n(C)c3n2)ccc1Br', 'CC(C)(C)c1ccc(C(=O)N[C@H]2CCN3CCCc4cccc2c43)cc1', "O=c1c2ccc3c(=O)n(-c4nccs4)c(=O)c4ccc(c(=O)n1-c1nccs1)c2c34", "O=C(N1CCc2c(F)ccc(F)c2C1)C1(O)Cc2ccccc2C1"]

    def tree_test():
        for s in sys.stdin:
            s = s.split()[0]
            tree = MolTree(s)
            print('-------------------------------------------')
            print(s)
            for node in tree.nodes:
                print(node.smiles, [x.smiles for x in node.neighbors])

    def decode_test():
        wrong = 0
        for tot,s in enumerate(sys.stdin):
            s = s.split()[0]
            tree = MolTree(s)
            tree.recover()

            cur_mol = copy_edit_mol(tree.nodes[0].mol)
            global_amap = [{}] + [{} for node in tree.nodes]
            global_amap[1] = {atom.GetIdx():atom.GetIdx() for atom in cur_mol.GetAtoms()}

            dfs_assemble(cur_mol, global_amap, [], tree.nodes[0], None)

            cur_mol = cur_mol.GetMol()
            cur_mol = Chem.MolFromSmiles(Chem.MolToSmiles(cur_mol))
            set_atommap(cur_mol)
            dec_smiles = Chem.MolToSmiles(cur_mol)

            gold_smiles = Chem.MolToSmiles(Chem.MolFromSmiles(s))
            if gold_smiles != dec_smiles:
                print(gold_smiles, dec_smiles)
                wrong += 1
            print(wrong, tot + 1)

    def enum_test():
        for s in sys.stdin:
            s = s.split()[0]
            tree = MolTree(s)
            tree.recover()
            tree.assemble()
            for node in tree.nodes:
                if node.label not in node.cands:
                    print(tree.smiles)
                    print(node.smiles, [x.smiles for x in node.neighbors])
                    print(node.label, len(node.cands))

    def count():
        cnt,n = 0,0
        for s in sys.stdin:
            s = s.split()[0]
            tree = MolTree(s)
            tree.recover()
            tree.assemble()
            for node in tree.nodes:
                cnt += len(node.cands)
            n += len(tree.nodes)
            #print cnt * 1.0 / n
    
    count()