def test(a_mol, b_smiles, transform):
a_prods = transform.RunReactants([a_mol])
if not a_prods:
return False
a_prods = [standardize(i) for i in chain(*a_prods)]
if not any(["[*]" in i for i in a_prods]):
if b_smiles in a_prods:
return True
return False
else:
qp = Chem.AdjustQueryParameters()
qp.makeDummiesQueries = True
qp.adjustDegree = True
qp.adjustDegreeFlags = Chem.ADJUST_IGNOREDUMMIES
a_prods = [Chem.AddHs(i) for i in a_prods]
a_prods = [Chem.AdjustQueryProperties(i, qp) for i in a_prods]
b_mol = Chem.MolFromSmiles(b_smiles)
b_mol = Chem.AddHs(b_mol)
if any([b_mol.HasSubstructMatch(i) for i in a_prods]):
return True
return False
def _load_template(self, path):
"""
Loads a template molecule with 2D coordinates
Args:
path (str): path to the model molecule in *.sdf,
or *.pdb format
Raises:
ValueError: if unsupported format is used: sdf|pdb
Returns:
rdkit.Chem.rdchem.Mol: RDKit representation of the template
"""
mol = Chem.RWMol()
extension = os.path.basename(path).split('.')[1]
if extension == 'sdf':
mol = Chem.MolFromMolFile(path, sanitize=True, removeHs=True)
elif extension == 'pdb':
mol = Chem.MolFromPDBFile(path, sanitize=True, removeHs=True)
else:
raise ValueError(
'Unsupported molecule type \'{}\''.format(extension))
p = Chem.AdjustQueryParameters()
p.makeAtomsGeneric = True
p.makeBondsGeneric = True
mol = Chem.AdjustQueryProperties(mol, p)
return mol
def __init__(self):
self.frag_list = list()
self.mol_list = list()
self.N_frag = 0
self.N_mol = 0
self.frag2mol = list()
self.mol2frag = list()
self.max_mol2frag = 0
self.max_frag2mol = 0
self.qp = Chem.AdjustQueryParameters()
self.frag2mol_mapping = list()
def _get_ligands(self):
ligands_df = pd.read_sql_query(
"""
select pdbid, mol_send(molecule) as molecule, atoms, rings, aromatic_rings, weight
from {ligands}
where molecule is not null
""".format(ligands=PopulateLigandsScript.LIGANDS_DB), self.conn)
params = Chem.AdjustQueryParameters()
params.makeAtomsGeneric = True
params.makeBondsGeneric = True
params.adjustRingCount = True
ligands_df.loc[:, "molecule"] = ligands_df.loc[:, "molecule"].apply(
lambda m: Chem.Mol(m.tobytes()))
ligands_df.loc[:, "pattern"] = ligands_df.loc[:, "molecule"].apply(
lambda m: Chem.AdjustQueryProperties(m, params))
return ligands_df
def align_mol_to_frags(smi_molecule, smi_linker, smi_frags):
try:
# Load SMILES as molecules
mol = Chem.MolFromSmiles(smi_molecule)
frags = Chem.MolFromSmiles(smi_frags)
linker = Chem.MolFromSmiles(smi_linker)
# Include dummy atoms in query
du = Chem.MolFromSmiles('*')
qp = Chem.AdjustQueryParameters()
qp.makeDummiesQueries = True
# Renumber molecule based on frags (incl. dummy atoms)
aligned_mols = []
sub_idx = []
# Get matches to fragments and linker
qfrag = Chem.AdjustQueryProperties(frags, qp)
frags_matches = list(mol.GetSubstructMatches(qfrag, uniquify=False))
qlinker = Chem.AdjustQueryProperties(linker, qp)
linker_matches = list(mol.GetSubstructMatches(qlinker, uniquify=False))
# Loop over matches
for frag_match, linker_match in product(frags_matches, linker_matches):
# Check if match
f_match = [
idx for num, idx in enumerate(frag_match)
if frags.GetAtomWithIdx(num).GetAtomicNum() != 0
]
l_match = [
idx for num, idx in enumerate(linker_match)
if linker.GetAtomWithIdx(num).GetAtomicNum() != 0
and idx not in f_match
]
# If perfect match, break
if len(set(list(f_match) +
list(l_match))) == mol.GetNumHeavyAtoms():
break
# Add frag indices
sub_idx += frag_match
# Add linker indices to end
sub_idx += [
idx for num, idx in enumerate(linker_match)
if linker.GetAtomWithIdx(num).GetAtomicNum() != 0
and idx not in sub_idx
]
aligned_mols.append(Chem.rdmolops.RenumberAtoms(mol, sub_idx))
aligned_mols.append(frags)
nodes_to_keep = [i for i in range(len(frag_match))]
# Renumber dummy atoms to end
dummy_idx = []
for atom in aligned_mols[1].GetAtoms():
if atom.GetAtomicNum() == 0:
dummy_idx.append(atom.GetIdx())
for i, mol in enumerate(aligned_mols):
sub_idx = list(range(aligned_mols[1].GetNumHeavyAtoms() + 2))
for idx in dummy_idx:
sub_idx.remove(idx)
sub_idx.append(idx)
if i == 0:
mol_range = list(range(mol.GetNumHeavyAtoms()))
else:
mol_range = list(range(mol.GetNumHeavyAtoms() + 2))
idx_to_add = list(set(mol_range).difference(set(sub_idx)))
sub_idx.extend(idx_to_add)
aligned_mols[i] = Chem.rdmolops.RenumberAtoms(mol, sub_idx)
# Get exit vectors
exit_vectors = []
for atom in aligned_mols[1].GetAtoms():
if atom.GetAtomicNum() == 0:
if atom.GetIdx() in nodes_to_keep:
nodes_to_keep.remove(atom.GetIdx())
for nei in atom.GetNeighbors():
exit_vectors.append(nei.GetIdx())
if len(exit_vectors) != 2:
print("Incorrect number of exit vectors")
return (aligned_mols[0], aligned_mols[1]), nodes_to_keep, exit_vectors
except:
print("Could not align")
return ([], []), [], []
def compute_distance_and_angle(mol, smi_linker, smi_frags):
try:
frags = [Chem.MolFromSmiles(frag) for frag in smi_frags.split(".")]
frags = Chem.MolFromSmiles(smi_frags)
linker = Chem.MolFromSmiles(smi_linker)
# Include dummy in query
du = Chem.MolFromSmiles('*')
qp = Chem.AdjustQueryParameters()
qp.makeDummiesQueries = True
# Renumber based on frags (incl. dummy atoms)
aligned_mols = []
sub_idx = []
# Align to frags and linker
qfrag = Chem.AdjustQueryProperties(frags, qp)
frags_matches = list(mol.GetSubstructMatches(qfrag, uniquify=False))
qlinker = Chem.AdjustQueryProperties(linker, qp)
linker_matches = list(mol.GetSubstructMatches(qlinker, uniquify=False))
# Loop over matches
for frag_match, linker_match in product(frags_matches, linker_matches):
# Check if match
f_match = [
idx for num, idx in enumerate(frag_match)
if frags.GetAtomWithIdx(num).GetAtomicNum() != 0
]
l_match = [
idx for num, idx in enumerate(linker_match)
if linker.GetAtomWithIdx(num).GetAtomicNum() != 0
and idx not in f_match
]
if len(set(list(f_match) +
list(l_match))) == mol.GetNumHeavyAtoms():
#if len(set(list(frag_match)+list(linker_match))) == mol.GetNumHeavyAtoms():
break
# Add frag indices
sub_idx += frag_match
# Add linker indices to end
sub_idx += [
idx for num, idx in enumerate(linker_match)
if linker.GetAtomWithIdx(num).GetAtomicNum() != 0
and idx not in sub_idx
]
nodes_to_keep = [i for i in range(len(frag_match))]
aligned_mols.append(Chem.rdmolops.RenumberAtoms(mol, sub_idx))
aligned_mols.append(frags)
# Renumber dummy atoms to end
dummy_idx = []
for atom in aligned_mols[1].GetAtoms():
if atom.GetAtomicNum() == 0:
dummy_idx.append(atom.GetIdx())
for i, mol in enumerate(aligned_mols):
sub_idx = list(range(aligned_mols[1].GetNumHeavyAtoms() + 2))
for idx in dummy_idx:
sub_idx.remove(idx)
sub_idx.append(idx)
if i == 0:
mol_range = list(range(mol.GetNumHeavyAtoms()))
else:
mol_range = list(range(mol.GetNumHeavyAtoms() + 2))
idx_to_add = list(set(mol_range).difference(set(sub_idx)))
sub_idx.extend(idx_to_add)
aligned_mols[i] = Chem.rdmolops.RenumberAtoms(mol, sub_idx)
# Get exit vectors
exit_vectors = []
linker_atom_idx = []
for atom in aligned_mols[1].GetAtoms():
if atom.GetAtomicNum() == 0:
if atom.GetIdx() in nodes_to_keep:
nodes_to_keep.remove(atom.GetIdx())
for nei in atom.GetNeighbors():
exit_vectors.append(nei.GetIdx())
linker_atom_idx.append(atom.GetIdx())
# Get coords
conf = aligned_mols[0].GetConformer()
exit_coords = []
for exit in exit_vectors:
exit_coords.append(np.array(conf.GetAtomPosition(exit)))
linker_coords = []
for linker_atom in linker_atom_idx:
linker_coords.append(np.array(conf.GetAtomPosition(linker_atom)))
# Get angle
v1_u = unit_vector(linker_coords[0] - exit_coords[0])
v2_u = unit_vector(linker_coords[1] - exit_coords[1])
angle = np.arccos(np.clip(np.dot(v1_u, v2_u), -1.0, 1.0))
# Get linker length
linker = Chem.MolFromSmiles(smi_linker)
linker_length = linker.GetNumHeavyAtoms()
# Get distance
distance = np.linalg.norm(exit_coords[0] - exit_coords[1])
# Record results
return distance, angle
except:
print(Chem.MolToSmiles(mol), smi_linker, smi_frags)
return None, None
def get_linker(full_mol, clean_frag, starting_point):
# INPUT FORMAT: molecule (RDKit mol object), clean fragments (RDKit mol object), starting fragments (SMILES)
# Get matches of fragments
matches = list(full_mol.GetSubstructMatches(clean_frag))
# If no matches, terminate
if len(matches) == 0:
print("No matches")
return ""
# Get number of atoms in linker
linker_len = full_mol.GetNumHeavyAtoms() - clean_frag.GetNumHeavyAtoms()
if linker_len == 0:
return ""
# Setup
mol_to_break = Chem.Mol(full_mol)
Chem.Kekulize(full_mol, clearAromaticFlags=True)
poss_linker = []
if len(matches) > 0:
# Loop over matches
for match in matches:
mol_rw = Chem.RWMol(full_mol)
# Get linker atoms
linker_atoms = list(
set(list(range(
full_mol.GetNumHeavyAtoms()))).difference(match))
linker_bonds = []
atoms_joined_to_linker = []
# Loop over starting fragments atoms
# Get (i) bonds between starting fragments and linker, (ii) atoms joined to linker
for idx_to_delete in sorted(match, reverse=True):
nei = [
x.GetIdx() for x in mol_rw.GetAtomWithIdx(
idx_to_delete).GetNeighbors()
]
intersect = set(nei).intersection(set(linker_atoms))
if len(intersect) == 1:
linker_bonds.append(
mol_rw.GetBondBetweenAtoms(
idx_to_delete,
list(intersect)[0]).GetIdx())
atoms_joined_to_linker.append(idx_to_delete)
elif len(intersect) > 1:
for idx_nei in list(intersect):
linker_bonds.append(
mol_rw.GetBondBetweenAtoms(idx_to_delete,
idx_nei).GetIdx())
atoms_joined_to_linker.append(idx_to_delete)
# Check number of atoms joined to linker
# If not == 2, check next match
if len(set(atoms_joined_to_linker)) != 2:
continue
# Delete starting fragments atoms
for idx_to_delete in sorted(match, reverse=True):
mol_rw.RemoveAtom(idx_to_delete)
linker = Chem.Mol(mol_rw)
# Check linker required num atoms
if linker.GetNumHeavyAtoms() == linker_len:
mol_rw = Chem.RWMol(full_mol)
# Delete linker atoms
for idx_to_delete in sorted(linker_atoms, reverse=True):
mol_rw.RemoveAtom(idx_to_delete)
frags = Chem.Mol(mol_rw)
# Check there are two disconnected fragments
if len(Chem.rdmolops.GetMolFrags(frags)) == 2:
# Fragment molecule into starting fragments and linker
fragmented_mol = Chem.FragmentOnBonds(
mol_to_break, linker_bonds)
# Remove starting fragments from fragmentation
linker_to_return = Chem.Mol(fragmented_mol)
qp = Chem.AdjustQueryParameters()
qp.makeDummiesQueries = True
for f in starting_point.split('.'):
qfrag = Chem.AdjustQueryProperties(
Chem.MolFromSmiles(f), qp)
linker_to_return = AllChem.DeleteSubstructs(
linker_to_return, qfrag, onlyFrags=True)
# Check linker is connected and two bonds to outside molecule
if len(Chem.rdmolops.GetMolFrags(linker)) == 1 and len(
linker_bonds) == 2:
Chem.Kekulize(linker_to_return,
clearAromaticFlags=True)
# If for some reason a starting fragment isn't removed (and it's larger than the linker), remove (happens v. occassionally)
if len(Chem.rdmolops.GetMolFrags(
linker_to_return)) > 1:
for frag in Chem.MolToSmiles(
linker_to_return).split('.'):
if Chem.MolFromSmiles(
frag).GetNumHeavyAtoms() == linker_len:
return frag
return Chem.MolToSmiles(
Chem.MolFromSmiles(
Chem.MolToSmiles(linker_to_return)))
# If not, add to possible linkers (above doesn't capture some complex cases)
else:
fragmented_mol = Chem.MolFromSmiles(
Chem.MolToSmiles(fragmented_mol), sanitize=False)
linker_to_return = AllChem.DeleteSubstructs(
fragmented_mol, Chem.MolFromSmiles(starting_point))
poss_linker.append(Chem.MolToSmiles(linker_to_return))
# If only one possibility, return linker
if len(poss_linker) == 1:
return poss_linker[0]
# If no possibilities, process failed
elif len(poss_linker) == 0:
print("FAIL:", Chem.MolToSmiles(full_mol),
Chem.MolToSmiles(clean_frag), starting_point)
return ""
# If multiple possibilities, process probably failed
else:
print("More than one poss linker. ", poss_linker)
return poss_linker[0]
def join_frag_linker(linker, st_pt, random_join=True):
if linker == "":
du = Chem.MolFromSmiles('*')
#print(Chem.MolToSmiles(Chem.RemoveHs(AllChem.ReplaceSubstructs(Chem.MolFromSmiles(st_pt),du,Chem.MolFromSmiles('[H]'),True)[0])).split('.')[0])
return Chem.MolToSmiles(
Chem.RemoveHs(
AllChem.ReplaceSubstructs(Chem.MolFromSmiles(st_pt), du,
Chem.MolFromSmiles('[H]'),
True)[0])).split('.')[0]
combo = Chem.CombineMols(Chem.MolFromSmiles(linker),
Chem.MolFromSmiles(st_pt))
# Include dummy in query
du = Chem.MolFromSmiles('*')
qp = Chem.AdjustQueryParameters()
qp.makeDummiesQueries = True
qlink = Chem.AdjustQueryProperties(Chem.MolFromSmiles(linker), qp)
linker_atoms = combo.GetSubstructMatches(qlink)
if len(linker_atoms) > 1:
for l_atoms in linker_atoms:
count_dummy = 0
for a in l_atoms:
if combo.GetAtomWithIdx(a).GetAtomicNum() == 0:
count_dummy += 1
if count_dummy == 2:
break
linker_atoms = l_atoms
else:
linker_atoms = linker_atoms[0]
linker_dummy_bonds = []
linker_dummy_bonds_at = []
linker_exit_points = []
for atom in linker_atoms:
if combo.GetAtomWithIdx(atom).GetAtomicNum() == 0:
linker_dummy_bonds.append(
combo.GetAtomWithIdx(atom).GetBonds()[0].GetIdx())
linker_dummy_bonds_at.append(
(atom, combo.GetAtomWithIdx(atom).GetNeighbors()[0].GetIdx()))
linker_exit_points.append(
combo.GetAtomWithIdx(atom).GetNeighbors()[0].GetIdx())
qst_pt = Chem.AdjustQueryProperties(Chem.MolFromSmiles(st_pt), qp)
st_pt_atoms = combo.GetSubstructMatches(qst_pt)
st_pt_atoms = list(
set(range(combo.GetNumAtoms())).difference(linker_atoms))
st_pt_dummy_bonds = []
st_pt_dummy_bonds_at = []
st_pt_exit_points = []
for atom in st_pt_atoms:
if combo.GetAtomWithIdx(atom).GetAtomicNum() == 0:
st_pt_dummy_bonds.append(
combo.GetAtomWithIdx(atom).GetBonds()[0].GetIdx())
st_pt_dummy_bonds_at.append(
(atom, combo.GetAtomWithIdx(atom).GetNeighbors()[0].GetIdx()))
st_pt_exit_points.append(
combo.GetAtomWithIdx(atom).GetNeighbors()[0].GetIdx())
combo_rw = Chem.EditableMol(combo)
if random_join:
np.random.shuffle(st_pt_exit_points)
for atom_1, atom_2 in zip(linker_exit_points, st_pt_exit_points):
if atom_1 == atom_2:
print(linker, st_pt)
break
combo_rw.AddBond(atom_1, atom_2, order=Chem.rdchem.BondType.SINGLE)
bonds_to_break = linker_dummy_bonds_at + st_pt_dummy_bonds_at
for bond in sorted(bonds_to_break, reverse=True):
combo_rw.RemoveBond(bond[0], bond[1])
final_mol = combo_rw.GetMol()
final_mol = sorted(Chem.MolToSmiles(final_mol).split('.'),
key=lambda x: len(x),
reverse=True)[0]
return final_mol
else:
final_mols = []
for st_pt_exit_pts in [st_pt_exit_points, st_pt_exit_points[::-1]]:
combo_rw = Chem.EditableMol(combo)
for atom_1, atom_2 in zip(linker_exit_points, st_pt_exit_pts):
if atom_1 == atom_2:
print(linker, st_pt)
break
combo_rw.AddBond(atom_1,
atom_2,
order=Chem.rdchem.BondType.SINGLE)
bonds_to_break = linker_dummy_bonds_at + st_pt_dummy_bonds_at
for bond in sorted(bonds_to_break, reverse=True):
combo_rw.RemoveBond(bond[0], bond[1])
final_mol = combo_rw.GetMol()
final_mol = sorted(Chem.MolToSmiles(final_mol).split('.'),
key=lambda x: len(x),
reverse=True)[0]
final_mols.append(final_mol)
return final_mols
