Mercurial > repos > bgruening > enumerate_charges
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"planemo upload for repository https://github.com/bgruening/galaxytools/tree/master/chemicaltoolbox/rdkit commit c1d813d3f0fec60ea6efe8a11e59d98bfdc1636f"
| author | bgruening |
|---|---|
| date | Sat, 04 Dec 2021 16:40:23 +0000 |
| parents | bbbf5fb356dd |
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# flake8: noqa # Copyright 2018 Jacob D. Durrant # # Licensed under the Apache License, Version 2.0 (the "License"); # you may not use this file except in compliance with the License. # You may obtain a copy of the License at # # http://www.apache.org/licenses/LICENSE-2.0 # # Unless required by applicable law or agreed to in writing, software # distributed under the License is distributed on an "AS IS" BASIS, # WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied. # See the License for the specific language governing permissions and # limitations under the License. """ This script identifies and enumerates the possible protonation sites of SMILES strings. """ from __future__ import print_function import argparse import os import sys try: # Python2 from StringIO import StringIO except ImportError: # Python3 from io import StringIO # Always let the user know a help file is available. print("\nFor help, use: python dimorphite_dl.py --help") # And always report citation information. print("\nIf you use Dimorphite-DL in your research, please cite:") print("Ropp PJ, Kaminsky JC, Yablonski S, Durrant JD (2019) Dimorphite-DL: An") print("open-source program for enumerating the ionization states of drug-like small") print("molecules. J Cheminform 11:14. doi:10.1186/s13321-019-0336-9.\n") try: import rdkit from rdkit import Chem from rdkit.Chem import AllChem except Exception: msg = "Dimorphite-DL requires RDKit. See https://www.rdkit.org/" print(msg) raise Exception(msg) def main(params=None): """The main definition run when you call the script from the commandline. :param params: The parameters to use. Entirely optional. If absent, defaults to None, in which case argments will be taken from those given at the command line. :param params: dict, optional :return: Returns a list of the SMILES strings return_as_list parameter is True. Otherwise, returns None. """ parser = ArgParseFuncs.get_args() args = vars(parser.parse_args()) # Add in any parameters in params. if params is not None: for k, v in params.items(): args[k] = v # If being run from the command line, print out all parameters. if __name__ == "__main__": print("\nPARAMETERS:\n") for k in sorted(args.keys()): print(k.rjust(13) + ": " + str(args[k])) print("") if args["test"]: # Run tests. TestFuncs.test() else: # Run protonation if "output_file" in args and args["output_file"] is not None: # An output file was specified, so write to that. with open(args["output_file"], "w") as file: for protonated_smi in Protonate(args): file.write(protonated_smi + "\n") elif "return_as_list" in args and args["return_as_list"]: return list(Protonate(args)) else: # No output file specified. Just print it to the screen. for protonated_smi in Protonate(args): print(protonated_smi) class MyParser(argparse.ArgumentParser): """Overwrite default parse so it displays help file on error. See https://stackoverflow.com/questions/4042452/display-help-message-with-python-argparse-when-script-is-called-without-any-argu""" def error(self, message): """Overwrites the default error message. :param message: The default error message. """ self.print_help() msg = "ERROR: %s\n\n" % message print(msg) raise Exception(msg) def print_help(self, file=None): """Overwrite the default print_help function :param file: Output file, defaults to None """ print("") if file is None: file = sys.stdout self._print_message(self.format_help(), file) print( """ examples: python dimorphite_dl.py --smiles_file sample_molecules.smi python dimorphite_dl.py --smiles "CCC(=O)O" --min_ph -3.0 --max_ph -2.0 python dimorphite_dl.py --smiles "CCCN" --min_ph -3.0 --max_ph -2.0 --output_file output.smi python dimorphite_dl.py --smiles_file sample_molecules.smi --pka_precision 2.0 --label_states python dimorphite_dl.py --test""" ) print("") class ArgParseFuncs: """A namespace for storing functions that are useful for processing command-line arguments. To keep things organized.""" @staticmethod def get_args(): """Gets the arguments from the command line. :return: A parser object. """ parser = MyParser( description="Dimorphite 1.2: Creates models of " + "appropriately protonated small moleucles. " + "Apache 2.0 License. Copyright 2018 Jacob D. " + "Durrant." ) parser.add_argument( "--min_ph", metavar="MIN", type=float, default=6.4, help="minimum pH to consider (default: 6.4)", ) parser.add_argument( "--max_ph", metavar="MAX", type=float, default=8.4, help="maximum pH to consider (default: 8.4)", ) parser.add_argument( "--pka_precision", metavar="PRE", type=float, default=1.0, help="pKa precision factor (number of standard devations, default: 1.0)", ) parser.add_argument( "--smiles", metavar="SMI", type=str, help="SMILES string to protonate" ) parser.add_argument( "--smiles_file", metavar="FILE", type=str, help="file that contains SMILES strings to protonate", ) parser.add_argument( "--output_file", metavar="FILE", type=str, help="output file to write protonated SMILES (optional)", ) parser.add_argument( "--label_states", action="store_true", help="label protonated SMILES with target state " + '(i.e., "DEPROTONATED", "PROTONATED", or "BOTH").', ) parser.add_argument( "--test", action="store_true", help="run unit tests (for debugging)" ) return parser @staticmethod def clean_args(args): """Cleans and normalizes input parameters :param args: A dictionary containing the arguments. :type args: dict :raises Exception: No SMILES in params. """ defaults = { "min_ph": 6.4, "max_ph": 8.4, "pka_precision": 1.0, "label_states": False, "test": False, } for key in defaults: if key not in args: args[key] = defaults[key] keys = list(args.keys()) for key in keys: if args[key] is None: del args[key] if not "smiles" in args and not "smiles_file" in args: msg = "Error: No SMILES in params. Use the -h parameter for help." print(msg) raise Exception(msg) # If the user provides a smiles string, turn it into a file-like StringIO # object. if "smiles" in args: if isinstance(args["smiles"], str): args["smiles_file"] = StringIO(args["smiles"]) args["smiles_and_data"] = LoadSMIFile(args["smiles_file"]) return args class UtilFuncs: """A namespace to store functions for manipulating mol objects. To keep things organized.""" @staticmethod def neutralize_mol(mol): """All molecules should be neuralized to the extent possible. The user should not be allowed to specify the valence of the atoms in most cases. :param rdkit.Chem.rdchem.Mol mol: The rdkit Mol objet to be neutralized. :return: The neutralized Mol object. """ # Get the reaction data rxn_data = [ [ "[Ov1-1:1]", "[Ov2+0:1]-[H]", ], # To handle O- bonded to only one atom (add hydrogen). [ "[#7v4+1:1]-[H]", "[#7v3+0:1]", ], # To handle N+ bonded to a hydrogen (remove hydrogen). [ "[Ov2-:1]", "[Ov2+0:1]", ], # To handle O- bonded to two atoms. Should not be Negative. [ "[#7v3+1:1]", "[#7v3+0:1]", ], # To handle N+ bonded to three atoms. Should not be positive. [ "[#7v2-1:1]", "[#7+0:1]-[H]", ], # To handle N- Bonded to two atoms. Add hydrogen. # ['[N:1]=[N+0:2]=[N:3]-[H]', '[N:1]=[N+1:2]=[N+0:3]-[H]'], # To # handle bad azide. Must be protonated. (Now handled elsewhere, before # SMILES converted to Mol object.) [ "[H]-[N:1]-[N:2]#[N:3]", "[N:1]=[N+1:2]=[N:3]-[H]", ], # To handle bad azide. R-N-N#N should be R-N=[N+]=N ] # Add substructures and reactions (initially none) for i, rxn_datum in enumerate(rxn_data): rxn_data[i].append(Chem.MolFromSmarts(rxn_datum[0])) rxn_data[i].append(None) # Add hydrogens (respects valence, so incomplete). # Chem.calcImplicitValence(mol) mol.UpdatePropertyCache(strict=False) mol = Chem.AddHs(mol) while True: # Keep going until all these issues have been resolved. current_rxn = None # The reaction to perform. current_rxn_str = None for i, rxn_datum in enumerate(rxn_data): ( reactant_smarts, product_smarts, substruct_match_mol, rxn_placeholder, ) = rxn_datum if mol.HasSubstructMatch(substruct_match_mol): if rxn_placeholder is None: current_rxn_str = reactant_smarts + ">>" + product_smarts current_rxn = AllChem.ReactionFromSmarts(current_rxn_str) rxn_data[i][3] = current_rxn # Update the placeholder. else: current_rxn = rxn_data[i][3] break # Perform the reaction if necessary if current_rxn is None: # No reaction left, so break out of while loop. break else: mol = current_rxn.RunReactants((mol,))[0][0] mol.UpdatePropertyCache(strict=False) # Update valences # The mols have been altered from the reactions described above, we need # to resanitize them. Make sure aromatic rings are shown as such This # catches all RDKit Errors. without the catchError and sanitizeOps the # Chem.SanitizeMol can crash the program. sanitize_string = Chem.SanitizeMol( mol, sanitizeOps=rdkit.Chem.rdmolops.SanitizeFlags.SANITIZE_ALL, catchErrors=True, ) return mol if sanitize_string.name == "SANITIZE_NONE" else None @staticmethod def convert_smiles_str_to_mol(smiles_str): """Given a SMILES string, check that it is actually a string and not a None. Then try to convert it to an RDKit Mol Object. :param string smiles_str: The SMILES string. :return: A rdkit.Chem.rdchem.Mol object, or None if it is the wrong type or if it fails to convert to a Mol Obj """ # Check that there are no type errors, ie Nones or non-string # A non-string type will cause RDKit to hard crash if smiles_str is None or type(smiles_str) is not str: return None # Try to fix azides here. They are just tricky to deal with. smiles_str = smiles_str.replace("N=N=N", "N=[N+]=N") smiles_str = smiles_str.replace("NN#N", "N=[N+]=N") # Now convert to a mol object. Note the trick that is necessary to # capture RDKit error/warning messages. See # https://stackoverflow.com/questions/24277488/in-python-how-to-capture-the-stdout-from-a-c-shared-library-to-a-variable stderr_fileno = sys.stderr.fileno() stderr_save = os.dup(stderr_fileno) stderr_pipe = os.pipe() os.dup2(stderr_pipe[1], stderr_fileno) os.close(stderr_pipe[1]) mol = Chem.MolFromSmiles(smiles_str) os.close(stderr_fileno) os.close(stderr_pipe[0]) os.dup2(stderr_save, stderr_fileno) os.close(stderr_save) # Check that there are None type errors Chem.MolFromSmiles has sanitize on # which means if there is even a small error in the SMILES (kekulize, # nitrogen charge...) then mol=None. ie. # Chem.MolFromSmiles("C[N]=[N]=[N]") = None this is an example of an # nitrogen charge error. It is cased in a try statement to be overly # cautious. return None if mol is None else mol @staticmethod def eprint(*args, **kwargs): """Error messages should be printed to STDERR. See https://stackoverflow.com/questions/5574702/how-to-print-to-stderr-in-python""" print(*args, file=sys.stderr, **kwargs) class LoadSMIFile(object): """A generator class for loading in the SMILES strings from a file, one at a time.""" def __init__(self, filename): """Initializes this class. :param filename: The filename or file object (i.e., StringIO). :type filename: str or StringIO """ if type(filename) is str: # It's a filename self.f = open(filename, "r") else: # It's a file object (i.e., StringIO) self.f = filename def __iter__(self): """Returns this generator object. :return: This generator object. :rtype: LoadSMIFile """ return self def __next__(self): """Ensure Python3 compatibility. :return: A dict, where the "smiles" key contains the canonical SMILES string and the "data" key contains the remaining information (e.g., the molecule name). :rtype: dict """ return self.next() def next(self): """Get the data associated with the next line. :raises StopIteration: If there are no more lines left iin the file. :return: A dict, where the "smiles" key contains the canonical SMILES string and the "data" key contains the remaining information (e.g., the molecule name). :rtype: dict """ line = self.f.readline() if line == "": # EOF self.f.close() raise StopIteration() return # Divide line into smi and data splits = line.split() if len(splits) != 0: # Generate mol object smiles_str = splits[0] # Convert from SMILES string to RDKIT Mol. This series of tests is # to make sure the SMILES string is properly formed and to get it # into a canonical form. Filter if failed. mol = UtilFuncs.convert_smiles_str_to_mol(smiles_str) if mol is None: UtilFuncs.eprint( "WARNING: Skipping poorly formed SMILES string: " + line ) return self.next() # Handle nuetralizing the molecules. Filter if failed. mol = UtilFuncs.neutralize_mol(mol) if mol is None: UtilFuncs.eprint( "WARNING: Skipping poorly formed SMILES string: " + line ) return self.next() # Remove the hydrogens. try: mol = Chem.RemoveHs(mol) except Exception: UtilFuncs.eprint( "WARNING: Skipping poorly formed SMILES string: " + line ) return self.next() if mol is None: UtilFuncs.eprint( "WARNING: Skipping poorly formed SMILES string: " + line ) return self.next() # Regenerate the smiles string (to standardize). new_mol_string = Chem.MolToSmiles(mol, isomericSmiles=True) return {"smiles": new_mol_string, "data": splits[1:]} else: # Blank line? Go to next one. return self.next() class Protonate(object): """A generator class for protonating SMILES strings, one at a time.""" def __init__(self, args): """Initialize the generator. :param args: A dictionary containing the arguments. :type args: dict """ # Make the args an object variable variable. self.args = args # A list to store the protonated SMILES strings associated with a # single input model. self.cur_prot_SMI = [] # Clean and normalize the args self.args = ArgParseFuncs.clean_args(args) # Load the substructures that can be protonated. self.subs = ProtSubstructFuncs.load_protonation_substructs_calc_state_for_ph( self.args["min_ph"], self.args["max_ph"], self.args["pka_precision"] ) def __iter__(self): """Returns this generator object. :return: This generator object. :rtype: Protonate """ return self def __next__(self): """Ensure Python3 compatibility. :return: A dict, where the "smiles" key contains the canonical SMILES string and the "data" key contains the remaining information (e.g., the molecule name). :rtype: dict """ return self.next() def next(self): """Get the next protonated SMILES string. :raises StopIteration: If there are no more lines left iin the file. :return: TODO A dict, where the "smiles" key contains the canonical SMILES string and the "data" key contains the remaining information (e.g., the molecule name). :rtype: dict """ # If there are any SMILES strings in self.cur_prot_SMI, just return # the first one and update the list to include only the remaining. if len(self.cur_prot_SMI) > 0: first, self.cur_prot_SMI = self.cur_prot_SMI[0], self.cur_prot_SMI[1:] return first # self.cur_prot_SMI is empty, so try to add more to it. # Get the next SMILES string from the input file. try: smile_and_datum = self.args["smiles_and_data"].next() except StopIteration: # There are no more input smiles strings... raise StopIteration() smi = smile_and_datum["smiles"] data = smile_and_datum["data"] # Everything on SMILES line but the # SMILES string itself (e.g., the # molecule name). # Collect the data associated with this smiles (e.g., the molecule # name). tag = " ".join(data) # sites is a list of (atom index, "PROTONATED|DEPROTONATED|BOTH"). # Note that the second entry indicates what state the site SHOULD be # in (not the one it IS in per the SMILES string). It's calculated # based on the probablistic distributions obtained during training. sites = ProtSubstructFuncs.get_prot_sites_and_target_states(smi, self.subs) new_smis = [smi] for site in sites: # Make a new smiles with the correct protonation state. Note that # new_smis is a growing list. This is how multiple protonation # sites are handled. # new_smis_to_perhaps_add = ProtSubstructFuncs.protonate_site(new_smis, site) new_smis = ProtSubstructFuncs.protonate_site(new_smis, site) # print(site, new_smis) # Good for debugging. # Only add new smiles if not already in the list. # for s in new_smis_to_perhaps_add: # if not s in new_smis: # new_smis.append(s) # In some cases, the script might generate redundant molecules. # Phosphonates, when the pH is between the two pKa values and the # stdev value is big enough, for example, will generate two identical # BOTH states. Let's remove this redundancy. new_smis = list(set(new_smis)) # Deprotonating protonated aromatic nitrogen gives [nH-]. Change this # to [n-]. This is a hack. new_smis = [s.replace("[nH-]", "[n-]") for s in new_smis] # Sometimes Dimorphite-DL generates molecules that aren't actually # possible. Simply convert these to mol objects to eliminate the bad # ones (that are None). new_smis = [ s for s in new_smis if UtilFuncs.convert_smiles_str_to_mol(s) is not None ] # If there are no smi left, return the input one at the very least. # All generated forms have apparently been judged # inappropriate/mal-formed. if len(new_smis) == 0: new_smis = [smi] # If the user wants to see the target states, add those # to the ends of each line. if self.args["label_states"]: states = "\t".join([x[1] for x in sites]) new_lines = [x + "\t" + tag + "\t" + states for x in new_smis] else: new_lines = [x + "\t" + tag for x in new_smis] self.cur_prot_SMI = new_lines return self.next() class ProtSubstructFuncs: """A namespace to store functions for loading the substructures that can be protonated. To keep things organized.""" @staticmethod def load_protonation_substructs_calc_state_for_ph( min_ph=6.4, max_ph=8.4, pka_std_range=1 ): """A pre-calculated list of R-groups with protonation sites, with their likely pKa bins. :param float min_ph: The lower bound on the pH range, defaults to 6.4. :param float max_ph: The upper bound on the pH range, defaults to 8.4. :param pka_std_range: Basically the precision (stdev from predicted pKa to consider), defaults to 1. :return: A dict of the protonation substructions for the specified pH range. """ subs = [] pwd = os.path.dirname(os.path.realpath(__file__)) site_structures_file = "{}/{}".format(pwd, "site_substructures.smarts") with open(site_structures_file, "r") as substruct: for line in substruct: line = line.strip() sub = {} if line is not "": splits = line.split() sub["name"] = splits[0] sub["smart"] = splits[1] sub["mol"] = Chem.MolFromSmarts(sub["smart"]) # NEED TO DIVIDE THIS BY 3s pka_ranges = [ splits[i : i + 3] for i in range(2, len(splits) - 1, 3) ] prot = [] for pka_range in pka_ranges: site = pka_range[0] std = float(pka_range[2]) * pka_std_range mean = float(pka_range[1]) protonation_state = ProtSubstructFuncs.define_protonation_state( mean, std, min_ph, max_ph ) prot.append([site, protonation_state]) sub["prot_states_for_pH"] = prot subs.append(sub) return subs @staticmethod def define_protonation_state(mean, std, min_ph, max_ph): """Updates the substructure definitions to include the protonation state based on the user-given pH range. The size of the pKa range is also based on the number of standard deviations to be considered by the user param. :param float mean: The mean pKa. :param float std: The precision (stdev). :param float min_ph: The min pH of the range. :param float max_ph: The max pH of the range. :return: A string describing the protonation state. """ min_pka = mean - std max_pka = mean + std # This needs to be reassigned, and 'ERROR' should never make it past the # next set of checks. if min_pka <= max_ph and min_ph <= max_pka: protonation_state = "BOTH" elif mean > max_ph: protonation_state = "PROTONATED" else: protonation_state = "DEPROTONATED" return protonation_state @staticmethod def get_prot_sites_and_target_states(smi, subs): """For a single molecule, find all possible matches in the protonation R-group list, subs. Items that are higher on the list will be matched first, to the exclusion of later items. :param string smi: A SMILES string. :param list subs: Substructure information. :return: A list of protonation sites and their pKa bin. ('PROTONATED', 'BOTH', or 'DEPROTONATED') """ # Convert the Smiles string (smi) to an RDKit Mol Obj mol = UtilFuncs.convert_smiles_str_to_mol(smi) # Check Conversion worked if mol is None: UtilFuncs.eprint("ERROR: ", smi) return [] # Try to Add hydrogens. if failed return [] try: mol = Chem.AddHs(mol) except Exception: UtilFuncs.eprint("ERROR: ", smi) return [] # Check adding Hs worked if mol is None: UtilFuncs.eprint("ERROR: ", smi) return [] ProtectUnprotectFuncs.unprotect_molecule(mol) protonation_sites = [] for item in subs: smart = item["mol"] if mol.HasSubstructMatch(smart): matches = ProtectUnprotectFuncs.get_unprotected_matches(mol, smart) prot = item["prot_states_for_pH"] for match in matches: # We want to move the site from being relative to the # substructure, to the index on the main molecule. for site in prot: proton = int(site[0]) category = site[1] new_site = (match[proton], category, item["name"]) if not new_site in protonation_sites: # Because sites must be unique. protonation_sites.append(new_site) ProtectUnprotectFuncs.protect_molecule(mol, match) return protonation_sites @staticmethod def protonate_site(smis, site): """Given a list of SMILES strings, we protonate the site. :param list smis: The list of SMILES strings. :param tuple site: Information about the protonation site. (idx, target_prot_state, prot_site_name) :return: A list of the appropriately protonated SMILES. """ # Decouple the atom index and its target protonation state from the site # tuple idx, target_prot_state, prot_site_name = site # Initialize the output list output_smis = [] state_to_charge = {"DEPROTONATED": [-1], "PROTONATED": [0], "BOTH": [-1, 0]} charges = state_to_charge[target_prot_state] # Now make the actual smiles match the target protonation state. output_smis = ProtSubstructFuncs.set_protonation_charge( smis, idx, charges, prot_site_name ) return output_smis @staticmethod def set_protonation_charge(smis, idx, charges, prot_site_name): """Sets the atomic charge on a particular site for a set of SMILES. :param list smis: A list of the SMILES strings. :param int idx: The index of the atom to consider. :param list charges: A list of the charges (ints) to assign at this site. :param string prot_site_name: The name of the protonation site. :return: A list of the processed SMILES strings. """ # Sets up the output list and the Nitrogen charge output = [] for charge in charges: # The charge for Nitrogens is 1 higher than others (i.e., protonated # state is positively charged). nitro_charge = charge + 1 # But there are a few nitrogen moieties where the acidic group is the # neutral one. Amides are a good example. I gave some thought re. how # to best flag these. I decided that those nitrogen-containing # moieties where the acidic group is neutral (rather than positively # charged) will have "*" in the name. if "*" in prot_site_name: nitro_charge = nitro_charge - 1 # Undo what was done previously. for smi in smis: # Convert smilesstring (smi) into a RDKit Mol mol = UtilFuncs.convert_smiles_str_to_mol(smi) # Check that the conversion worked, skip if it fails if mol is None: continue atom = mol.GetAtomWithIdx(idx) # Assign the protonation charge, with special care for Nitrogens element = atom.GetAtomicNum() if element == 7: atom.SetFormalCharge(nitro_charge) else: atom.SetFormalCharge(charge) # Convert back to SMILE and add to output out_smile = Chem.MolToSmiles(mol, isomericSmiles=True, canonical=True) output.append(out_smile) return output class ProtectUnprotectFuncs: """A namespace for storing functions that are useful for protecting and unprotecting molecules. To keep things organized. We need to identify and mark groups that have been matched with a substructure.""" @staticmethod def unprotect_molecule(mol): """Sets the protected property on all atoms to 0. This also creates the property for new molecules. :param rdkit.Chem.rdchem.Mol mol: The rdkit Mol object. :type mol: The rdkit Mol object with atoms unprotected. """ for atom in mol.GetAtoms(): atom.SetProp("_protected", "0") @staticmethod def protect_molecule(mol, match): """Given a 'match', a list of molecules idx's, we set the protected status of each atom to 1. This will prevent any matches using that atom in the future. :param rdkit.Chem.rdchem.Mol mol: The rdkit Mol object to protect. :param list match: A list of molecule idx's. """ for idx in match: atom = mol.GetAtomWithIdx(idx) atom.SetProp("_protected", "1") @staticmethod def get_unprotected_matches(mol, substruct): """Finds substructure matches with atoms that have not been protected. Returns list of matches, each match a list of atom idxs. :param rdkit.Chem.rdchem.Mol mol: The Mol object to consider. :param string substruct: The SMARTS string of the substructure ot match. :return: A list of the matches. Each match is itself a list of atom idxs. """ matches = mol.GetSubstructMatches(substruct) unprotected_matches = [] for match in matches: if ProtectUnprotectFuncs.is_match_unprotected(mol, match): unprotected_matches.append(match) return unprotected_matches @staticmethod def is_match_unprotected(mol, match): """Checks a molecule to see if the substructure match contains any protected atoms. :param rdkit.Chem.rdchem.Mol mol: The Mol object to check. :param list match: The match to check. :return: A boolean, whether the match is present or not. """ for idx in match: atom = mol.GetAtomWithIdx(idx) protected = atom.GetProp("_protected") if protected == "1": return False return True class TestFuncs: """A namespace for storing functions that perform tests on the code. To keep things organized.""" @staticmethod def test(): """Tests all the 38 groups.""" smis = [ # [input smiles, pka, protonated, deprotonated, category] ["C#CCO", "C#CCO", "C#CC[O-]", "Alcohol"], ["C(=O)N", "NC=O", "[NH-]C=O", "Amide"], [ "CC(=O)NOC(C)=O", "CC(=O)NOC(C)=O", "CC(=O)[N-]OC(C)=O", "Amide_electronegative", ], ["COC(=N)N", "COC(N)=[NH2+]", "COC(=N)N", "AmidineGuanidine2"], [ "Brc1ccc(C2NCCS2)cc1", "Brc1ccc(C2[NH2+]CCS2)cc1", "Brc1ccc(C2NCCS2)cc1", "Amines_primary_secondary_tertiary", ], [ "CC(=O)[n+]1ccc(N)cc1", "CC(=O)[n+]1ccc([NH3+])cc1", "CC(=O)[n+]1ccc(N)cc1", "Anilines_primary", ], ["CCNc1ccccc1", "CC[NH2+]c1ccccc1", "CCNc1ccccc1", "Anilines_secondary"], [ "Cc1ccccc1N(C)C", "Cc1ccccc1[NH+](C)C", "Cc1ccccc1N(C)C", "Anilines_tertiary", ], [ "BrC1=CC2=C(C=C1)NC=C2", "Brc1ccc2[nH]ccc2c1", "Brc1ccc2[n-]ccc2c1", "Indole_pyrrole", ], [ "O=c1cc[nH]cc1", "O=c1cc[nH]cc1", "O=c1cc[n-]cc1", "Aromatic_nitrogen_protonated", ], ["C-N=[N+]=[N@H]", "CN=[N+]=N", "CN=[N+]=[N-]", "Azide"], ["BrC(C(O)=O)CBr", "O=C(O)C(Br)CBr", "O=C([O-])C(Br)CBr", "Carboxyl"], ["NC(NN=O)=N", "NC(=[NH2+])NN=O", "N=C(N)NN=O", "AmidineGuanidine1"], [ "C(F)(F)(F)C(=O)NC(=O)C", "CC(=O)NC(=O)C(F)(F)F", "CC(=O)[N-]C(=O)C(F)(F)F", "Imide", ], ["O=C(C)NC(C)=O", "CC(=O)NC(C)=O", "CC(=O)[N-]C(C)=O", "Imide2"], [ "CC(C)(C)C(N(C)O)=O", "CN(O)C(=O)C(C)(C)C", "CN([O-])C(=O)C(C)(C)C", "N-hydroxyamide", ], ["C[N+](O)=O", "C[N+](=O)O", "C[N+](=O)[O-]", "Nitro"], ["O=C1C=C(O)CC1", "O=C1C=C(O)CC1", "O=C1C=C([O-])CC1", "O=C-C=C-OH"], ["C1CC1OO", "OOC1CC1", "[O-]OC1CC1", "Peroxide2"], ["C(=O)OO", "O=COO", "O=CO[O-]", "Peroxide1"], [ "Brc1cc(O)cc(Br)c1", "Oc1cc(Br)cc(Br)c1", "[O-]c1cc(Br)cc(Br)c1", "Phenol", ], [ "CC(=O)c1ccc(S)cc1", "CC(=O)c1ccc(S)cc1", "CC(=O)c1ccc([S-])cc1", "Phenyl_Thiol", ], [ "C=CCOc1ccc(C(=O)O)cc1", "C=CCOc1ccc(C(=O)O)cc1", "C=CCOc1ccc(C(=O)[O-])cc1", "Phenyl_carboxyl", ], ["COP(=O)(O)OC", "COP(=O)(O)OC", "COP(=O)([O-])OC", "Phosphate_diester"], ["CP(C)(=O)O", "CP(C)(=O)O", "CP(C)(=O)[O-]", "Phosphinic_acid"], [ "CC(C)OP(C)(=O)O", "CC(C)OP(C)(=O)O", "CC(C)OP(C)(=O)[O-]", "Phosphonate_ester", ], [ "CC1(C)OC(=O)NC1=O", "CC1(C)OC(=O)NC1=O", "CC1(C)OC(=O)[N-]C1=O", "Ringed_imide1", ], ["O=C(N1)C=CC1=O", "O=C1C=CC(=O)N1", "O=C1C=CC(=O)[N-]1", "Ringed_imide2"], ["O=S(OC)(O)=O", "COS(=O)(=O)O", "COS(=O)(=O)[O-]", "Sulfate"], [ "COc1ccc(S(=O)O)cc1", "COc1ccc(S(=O)O)cc1", "COc1ccc(S(=O)[O-])cc1", "Sulfinic_acid", ], ["CS(N)(=O)=O", "CS(N)(=O)=O", "CS([NH-])(=O)=O", "Sulfonamide"], [ "CC(=O)CSCCS(O)(=O)=O", "CC(=O)CSCCS(=O)(=O)O", "CC(=O)CSCCS(=O)(=O)[O-]", "Sulfonate", ], ["CC(=O)S", "CC(=O)S", "CC(=O)[S-]", "Thioic_acid"], ["C(C)(C)(C)(S)", "CC(C)(C)S", "CC(C)(C)[S-]", "Thiol"], [ "Brc1cc[nH+]cc1", "Brc1cc[nH+]cc1", "Brc1ccncc1", "Aromatic_nitrogen_unprotonated", ], [ "C=C(O)c1c(C)cc(C)cc1C", "C=C(O)c1c(C)cc(C)cc1C", "C=C([O-])c1c(C)cc(C)cc1C", "Vinyl_alcohol", ], ["CC(=O)ON", "CC(=O)O[NH3+]", "CC(=O)ON", "Primary_hydroxyl_amine"], ] smis_phos = [ [ "O=P(O)(O)OCCCC", "CCCCOP(=O)(O)O", "CCCCOP(=O)([O-])O", "CCCCOP(=O)([O-])[O-]", "Phosphate", ], [ "CC(P(O)(O)=O)C", "CC(C)P(=O)(O)O", "CC(C)P(=O)([O-])O", "CC(C)P(=O)([O-])[O-]", "Phosphonate", ], ] # Load the average pKa values. average_pkas = { l.split()[0].replace("*", ""): float(l.split()[3]) for l in open("site_substructures.smarts") if l.split()[0] not in ["Phosphate", "Phosphonate"] } average_pkas_phos = { l.split()[0].replace("*", ""): [float(l.split()[3]), float(l.split()[6])] for l in open("site_substructures.smarts") if l.split()[0] in ["Phosphate", "Phosphonate"] } print("Running Tests") print("=============") print("") print("Very Acidic (pH -10000000)") print("--------------------------") print("") args = { "min_ph": -10000000, "max_ph": -10000000, "pka_precision": 0.5, "smiles": "", "label_states": True, } for smi, protonated, deprotonated, category in smis: args["smiles"] = smi TestFuncs.test_check(args, [protonated], ["PROTONATED"]) for smi, protonated, mix, deprotonated, category in smis_phos: args["smiles"] = smi TestFuncs.test_check(args, [protonated], ["PROTONATED"]) args["min_ph"] = 10000000 args["max_ph"] = 10000000 print("") print("Very Basic (pH 10000000)") print("------------------------") print("") for smi, protonated, deprotonated, category in smis: args["smiles"] = smi TestFuncs.test_check(args, [deprotonated], ["DEPROTONATED"]) for smi, protonated, mix, deprotonated, category in smis_phos: args["smiles"] = smi TestFuncs.test_check(args, [deprotonated], ["DEPROTONATED"]) print("") print("pH is Category pKa") print("------------------") print("") for smi, protonated, deprotonated, category in smis: avg_pka = average_pkas[category] args["smiles"] = smi args["min_ph"] = avg_pka args["max_ph"] = avg_pka TestFuncs.test_check(args, [protonated, deprotonated], ["BOTH"]) for smi, protonated, mix, deprotonated, category in smis_phos: args["smiles"] = smi avg_pka = average_pkas_phos[category][0] args["min_ph"] = avg_pka args["max_ph"] = avg_pka TestFuncs.test_check(args, [mix, protonated], ["BOTH"]) avg_pka = average_pkas_phos[category][1] args["min_ph"] = avg_pka args["max_ph"] = avg_pka TestFuncs.test_check( args, [mix, deprotonated], ["DEPROTONATED", "DEPROTONATED"] ) avg_pka = 0.5 * ( average_pkas_phos[category][0] + average_pkas_phos[category][1] ) args["min_ph"] = avg_pka args["max_ph"] = avg_pka args["pka_precision"] = 5 # Should give all three TestFuncs.test_check( args, [mix, deprotonated, protonated], ["BOTH", "BOTH"] ) @staticmethod def test_check(args, expected_output, labels): """Tests most ionizable groups. The ones that can only loose or gain a single proton. :param args: The arguments to pass to protonate() :param expected_output: A list of the expected SMILES-strings output. :param labels: The labels. A list containing combo of BOTH, PROTONATED, DEPROTONATED. :raises Exception: Wrong number of states produced. :raises Exception: Unexpected output SMILES. :raises Exception: Wrong labels. """ output = list(Protonate(args)) output = [o.split() for o in output] num_states = len(expected_output) if len(output) != num_states: msg = ( args["smiles"] + " should have " + str(num_states) + " states at at pH " + str(args["min_ph"]) + ": " + str(output) ) print(msg) raise Exception(msg) if len(set([l[0] for l in output]) - set(expected_output)) != 0: msg = ( args["smiles"] + " is not " + " AND ".join(expected_output) + " at pH " + str(args["min_ph"]) + " - " + str(args["max_ph"]) + "; it is " + " AND ".join([l[0] for l in output]) ) print(msg) raise Exception(msg) if len(set([l[1] for l in output]) - set(labels)) != 0: msg = ( args["smiles"] + " not labeled as " + " AND ".join(labels) + "; it is " + " AND ".join([l[1] for l in output]) ) print(msg) raise Exception(msg) ph_range = sorted(list(set([args["min_ph"], args["max_ph"]]))) ph_range_str = "(" + " - ".join("{0:.2f}".format(n) for n in ph_range) + ")" print( "(CORRECT) " + ph_range_str.ljust(10) + " " + args["smiles"] + " => " + " AND ".join([l[0] for l in output]) ) def run(**kwargs): """A helpful, importable function for those who want to call Dimorphite-DL from another Python script rather than the command line. Note that this function accepts keyword arguments that match the command-line parameters exactly. If you want to pass and return a list of RDKit Mol objects, import run_with_mol_list() instead. :param **kwargs: For a complete description, run dimorphite_dl.py from the command line with the -h option. :type kwargs: dict """ # Run the main function with the specified arguments. main(kwargs) def run_with_mol_list(mol_lst, **kwargs): """A helpful, importable function for those who want to call Dimorphite-DL from another Python script rather than the command line. Note that this function is for passing Dimorphite-DL a list of RDKit Mol objects, together with command-line parameters. If you want to use only the same parameters that you would use from the command line, import run() instead. :param mol_lst: A list of rdkit.Chem.rdchem.Mol objects. :type mol_lst: list :raises Exception: If the **kwargs includes "smiles", "smiles_file", "output_file", or "test" parameters. :return: A list of properly protonated rdkit.Chem.rdchem.Mol objects. :rtype: list """ # Do a quick check to make sure the user input makes sense. for bad_arg in ["smiles", "smiles_file", "output_file", "test"]: if bad_arg in kwargs: msg = ( "You're using Dimorphite-DL's run_with_mol_list(mol_lst, " + '**kwargs) function, but you also passed the "' + bad_arg + '" argument. Did you mean to use the ' + "run(**kwargs) function instead?" ) print(msg) raise Exception(msg) # Set the return_as_list flag so main() will return the protonated smiles # as a list. kwargs["return_as_list"] = True # Having reviewed the code, it will be very difficult to rewrite it so # that a list of Mol objects can be used directly. Intead, convert this # list of mols to smiles and pass that. Not efficient, but it will work. protonated_smiles_and_props = [] for m in mol_lst: props = m.GetPropsAsDict() kwargs["smiles"] = Chem.MolToSmiles(m, isomericSmiles=True) protonated_smiles_and_props.extend( [(s.split("\t")[0], props) for s in main(kwargs)] ) # Now convert the list of protonated smiles strings back to RDKit Mol # objects. Also, add back in the properties from the original mol objects. mols = [] for s, props in protonated_smiles_and_props: m = Chem.MolFromSmiles(s) if m: for prop, val in props.items(): if type(val) is int: m.SetIntProp(prop, val) elif type(val) is float: m.SetDoubleProp(prop, val) elif type(val) is bool: m.SetBoolProp(prop, val) else: m.SetProp(prop, str(val)) mols.append(m) else: UtilFuncs.eprint( "WARNING: Could not process molecule with SMILES string " + s + " and properties " + str(props) ) return mols if __name__ == "__main__": main()