Mercurial > repos > bgruening > rdconf
diff dimorphite_dl.py @ 0:55a2082540a9 draft default tip
"planemo upload for repository https://github.com/bgruening/galaxytools/tree/master/chemicaltoolbox/rdkit commit c1d813d3f0fec60ea6efe8a11e59d98bfdc1636f"
| author | bgruening |
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| date | Sat, 04 Dec 2021 16:36:56 +0000 |
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--- /dev/null Thu Jan 01 00:00:00 1970 +0000 +++ b/dimorphite_dl.py Sat Dec 04 16:36:56 2021 +0000 @@ -0,0 +1,1311 @@ +# 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()