Mercurial > repos > bgruening > ctb_rdkit_descriptors
changeset 4:414edd9ea77d draft
"planemo upload for repository https://github.com/bgruening/galaxytools/tree/master/chemicaltoolbox/rdkit commit 20df7e562341cd30e89a14d6bde9054956fadc06"
| author | bgruening |
|---|---|
| date | Tue, 10 Mar 2020 12:58:24 -0400 |
| parents | 617d4555d8d3 |
| children | 1cf3bab54ddd |
| files | dimorphite_dl.py site_substructures.smarts test-data/mols.smi |
| diffstat | 3 files changed, 1126 insertions(+), 0 deletions(-) [+] |
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--- /dev/null Thu Jan 01 00:00:00 1970 +0000 +++ b/dimorphite_dl.py Tue Mar 10 12:58:24 2020 -0400 @@ -0,0 +1,1084 @@ +# 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 copy +import os +import argparse +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: + 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"] == True: + 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: + 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: + 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()
--- /dev/null Thu Jan 01 00:00:00 1970 +0000 +++ b/site_substructures.smarts Tue Mar 10 12:58:24 2020 -0400 @@ -0,0 +1,39 @@ +*Azide [N+0:1]=[N+:2]=[N+0:3]-[H] 2 4.65 0.07071067811865513 +Nitro [C,c,N,n,O,o:1]-[NX3:2](=[O:3])-[O:4]-[H] 3 -1000.0 0 +AmidineGuanidine1 [N:1]-[C:2](-[N:3])=[NX2:4]-[H:5] 3 12.025333333333334 1.5941046150769165 +AmidineGuanidine2 [C:1](-[N:2])=[NX2+0:3] 2 10.035538461538462 2.1312826469414716 +Sulfate [SX4:1](=[O:2])(=[O:3])([O:4]-[C,c,N,n:5])-[OX2:6]-[H] 5 -2.36 1.3048043093561141 +Sulfonate [SX4:1](=[O:2])(=[O:3])(-[C,c,N,n:4])-[OX2:5]-[H] 4 -1.8184615384615386 1.4086213481855594 +Sulfinic_acid [SX3:1](=[O:2])-[O:3]-[H] 2 1.7933333333333332 0.4372070447739835 +Phenyl_carboxyl [c,n,o:1]-[C:2](=[O:3])-[O:4]-[H] 3 3.463441968255319 1.2518054407928614 +Carboxyl [C:1](=[O:2])-[O:3]-[H] 2 3.456652971502591 1.2871420886834017 +Thioic_acid [C,c,N,n:1](=[O,S:2])-[SX2,OX2:3]-[H] 2 0.678267 1.497048763660801 +Phenyl_Thiol [c,n:1]-[SX2:2]-[H] 1 4.978235294117647 2.6137000480499806 +Thiol [C,N:1]-[SX2:2]-[H] 1 9.12448275862069 1.3317968158171463 +Phosphate [PX4:1](=[O:2])(-[OX2:3]-[H])(-[O+0:4])-[OX2:5]-[H] 2 2.4182608695652172 1.1091177991945305 5 6.5055 0.9512787792174668 +Phosphonate [PX4:1](=[O:2])(-[OX2:3]-[H])(-[C,c,N,n:4])-[OX2:5]-[H] 2 1.8835714285714287 0.5925999820080644 5 7.247254901960784 0.8511476450801531 +Phenol [c,n,o:1]-[O:2]-[H] 1 7.065359866910526 3.277356122295936 +Peroxide1 [O:1]([$(C=O),$(C[Cl]),$(CF),$(C[Br]),$(CC#N):2])-[O:3]-[H] 2 8.738888888888889 0.7562592839596507 +Peroxide2 [C:1]-[O:2]-[O:3]-[H] 2 11.978235294117647 0.8697645895163075 +O=C-C=C-OH [O:1]=[C;R:2]-[C;R:3]=[C;R:4]-[O:5]-[H] 4 3.554 0.803339458581667 +Vinyl_alcohol [C:1]=[C:2]-[O:3]-[H] 2 8.871850714285713 1.660200255394124 +Alcohol [C:1]-[O:2]-[H] 1 14.780384615384616 2.546464970533435 +N-hydroxyamide [C:1](=[O:2])-[N:3]-[O:4]-[H] 3 9.301904761904762 1.2181897185891002 +*Ringed_imide1 [O,S:1]=[C;R:2]([$([#8]),$([#7]),$([#16]),$([#6][Cl]),$([#6]F),$([#6][Br]):3])-[N;R:4]([C;R:5]=[O,S:6])-[H] 3 6.4525 0.5555627777308341 +*Ringed_imide2 [O,S:1]=[C;R:2]-[N;R:3]([C;R:4]=[O,S:5])-[H] 2 8.681666666666667 1.8657779975741713 +*Imide [F,Cl,Br,S,s,P,p:1][#6:2][CX3:3](=[O,S:4])-[NX3+0:5]([CX3:6]=[O,S:7])-[H] 4 2.466666666666667 1.4843629385474877 +*Imide2 [O,S:1]=[CX3:2]-[NX3+0:3]([CX3:4]=[O,S:5])-[H] 2 10.23 1.1198214143335534 +*Amide_electronegative [C:1](=[O:2])-[N:3](-[Br,Cl,I,F,S,O,N,P:4])-[H] 2 3.4896 2.688124315081677 +*Amide [C:1](=[O:2])-[N:3]-[H] 2 12.00611111111111 4.512491341218857 +*Sulfonamide [SX4:1](=[O:2])(=[O:3])-[NX3+0:4]-[H] 3 7.9160326086956525 1.9842121316708763 +Anilines_primary [c:1]-[NX3+0:2]([H:3])[H:4] 1 3.899298673194805 2.068768503987161 +Anilines_secondary [c:1]-[NX3+0:2]([H:3])[!H:4] 1 4.335408163265306 2.1768842022330843 +Anilines_tertiary [c:1]-[NX3+0:2]([!H:3])[!H:4] 1 4.16690685045614 2.005865735782679 +Aromatic_nitrogen_unprotonated [n+0&H0:1] 0 4.3535441240733945 2.0714072661859584 +Amines_primary_secondary_tertiary [C:1]-[NX3+0:2] 1 8.159107682388349 2.5183597445318147 +Phosphinic_acid [PX4:1](=[O:2])(-[C,c,N,n,F,Cl,Br,I:3])(-[C,c,N,n,F,Cl,Br,I:4])-[OX2:5]-[H] 4 2.9745 0.6867886750744557 +Phosphate_diester [PX4:1](=[O:2])(-[OX2:3]-[C,c,N,n,F,Cl,Br,I:4])(-[O+0:5]-[C,c,N,n,F,Cl,Br,I:4])-[OX2:6]-[H] 6 2.7280434782608696 2.5437448856908316 +Phosphonate_ester [PX4:1](=[O:2])(-[OX2:3]-[C,c,N,n,F,Cl,Br,I:4])(-[C,c,N,n,F,Cl,Br,I:5])-[OX2:6]-[H] 5 2.0868 0.4503028610465036 +Primary_hydroxyl_amine [C,c:1]-[O:2]-[NH2:3] 2 4.035714285714286 0.8463816543155368 +*Indole_pyrrole [c;R:1]1[c;R:2][c;R:3][c;R:4][n;R:5]1[H] 4 14.52875 4.06702491591416 +*Aromatic_nitrogen_protonated [n:1]-[H] 0 7.17 2.94602395490212