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import logging
import random
from typing import List, Tuple, Callable, Any, Union, Dict, Optional, Literal
from functools import lru_cache
from rdkit import Chem
from rdkit.Chem import AllChem
from rdkit.Chem import rdchem
from rdkit import RDLogger
from rdkit.Chem import CanonSmiles
from .chemoinformatics import (
canonize,
smiles2mol,
)
RDLogger.DisableLog("rdApp.*")
@lru_cache(maxsize=None)
def get_mol(smiles: str) -> rdchem.Mol:
return Chem.MolFromSmiles(smiles)
def find_atom_idx_of_map_atoms(
mol: rdchem.Mol,
find_poi: True,
find_e3: True,
poi_attachment_id: int = 1,
e3_attachment_id: int = 2,
) -> Union[int, Tuple[int, int]]:
""" Find the indices of the attachment points in the given molecule.
Args:
mol (rdkit.Chem.rdchem.Mol): The molecule.
find_poi (bool): Whether to find the POI attachment point.
find_e3 (bool): Whether to find the E3 attachment point.
poi_attachment_id (int): The label of the attachment point for the POI ligand, i.e., "[*:{poi_attachment_id}]".
e3_attachment_id (int): The label of the attachment point for the E3 binder, i.e., "[*:{e3_attachment_id}]".
Returns:
int | Tuple[int, int]: The index of the attachment point for the POI ligand if find_poi is True, the index of the attachment point for the E3 binder if find_e3 is True, or a tuple containing POI and E3 indices (in this order) if both find_poi and find_e3 are True.
"""
if find_poi and find_e3:
poi_idx = None
e3_idx = None
for atom in mol.GetAtoms():
if atom.GetAtomMapNum() == poi_attachment_id:
poi_idx = atom.GetIdx()
elif atom.GetAtomMapNum() == e3_attachment_id:
e3_idx = atom.GetIdx()
if poi_idx is not None and e3_idx is not None:
break
return poi_idx, e3_idx
elif find_poi:
for atom in mol.GetAtoms():
if atom.GetAtomMapNum() == poi_attachment_id:
return atom.GetIdx()
elif find_e3:
for atom in mol.GetAtoms():
if atom.GetAtomMapNum() == e3_attachment_id:
return atom.GetIdx()
def reassemble_protac(
ligands_smiles: Optional[str] = None,
poi_smiles: Optional[str] = None,
linker_smiles: Optional[str] = None,
e3_smiles: Optional[str] = None,
e3_bond_type: Literal['single', 'double', 'triple', 'rand_uniform'] = 'single',
poi_bond_type: Literal['single', 'double', 'triple', 'rand_uniform'] = 'single',
poi_attachment_id: int = 1,
e3_attachment_id: int = 2,
rand_generator = None,
) -> Tuple[str, Chem.rdchem.Mol]:
""" Reassemble a PROTAC molecule from its substructures. The SMILES must contain attachment points.
In case the bond type cannot be formed an error will be raised.
Example of usage:
```python
e3_smiles = '[*:2]NC(C(=O)N1CC(O)CC1C(=O)NCc1ccc(-c2scnc2C)cc1)C(C)(C)C'
linker_smiles = '[*:2]C(=O)CCCCCCCCCC[*:1]'
poi_smiles = '[*:1]CN1CCN(c2ccc(Nc3ncc4c(C)cc(=O)n(-c5cccc(NC(=O)C=C)c5)c4n3)c(OC)c2)CC1'
merged_smiles, _ = reassemble_protac(poi_smiles, linker_smiles, e3_smiles, 'single', 'single')
print(merged_smiles)
```
Args:
poi_smiles (str): The SMILES notation for the POI ligand.
linker_smiles (str): The SMILES notation for the linker.
e3_smiles (str): The SMILES notation for the E3 binder.
e3_bond_type (str): The type of bond to be added between the E3 binder and the linker. Can be 'single', 'double', 'triple', or 'rand_uniform'.
poi_bond_type (str): The type of bond to be added between the POI ligand and the linker. Can be 'single', 'double', 'triple', or 'rand_uniform'.
poi_attachment_id (int): The label of the attachment point for the POI ligand, i.e., "[*:{poi_attachment_id}]".
e3_attachment_id (int): The label of the attachment point for the E3 binder, i.e., "[*:{e3_attachment_id}]".
rand_generator: A random number generator for 'rand_uniform' bond types. Defaults to None, i.e., standard library random.
Returns:
Tuple[str, Chem.rdchem.Mol]: The SMILES notation and RDKit molecule object for the reassembled PROTAC molecule.
"""
if ligands_smiles is None:
if None in [poi_smiles, linker_smiles, e3_smiles]:
raise ValueError("Missing substructures SMILES: either provide ligands_smiles or all of poi_smiles, linker_smiles, and e3_smiles")
ligands_smiles = f'{e3_smiles}.{linker_smiles}.{poi_smiles}'
if None in [poi_smiles, linker_smiles, e3_smiles]:
if ligands_smiles is None:
raise ValueError("Missing substructures SMILES: either provide ligands_smiles or all of poi_smiles, linker_smiles, and e3_smiles")
ligands_mol = canonize(smiles2mol(ligands_smiles))
if ligands_mol is None:
return None, None
try:
protac_mol = Chem.molzip(ligands_mol)
except ValueError as e:
logging.error(f"Failed to reassemble PROTAC: {e}")
return None, None |