run.py

import argparse

PARSER = argparse.ArgumentParser()

# Allows the run commands to be submitted via a .json file.
PARSER.add_argument(
    "--json",
    "-j",
    metavar="param.json",
    help="Name of a json file containing all parameters. \
    Overrides other arguments.",
)

# Allows the run in debug mode. Doesn't delete temp files.
PARSER.add_argument(
    "--debug_mode",
    "-d",
    action="store_true",
    default=False,
    help="Run Autogrow in Debug mode. This keeps all \
    temporary files and adds extra print statements.",
)

# receptor information
PARSER.add_argument(
    "--filename_of_receptor",
    "-r",
    metavar="receptor.pdb",
    default='./tutorial/PARP/4r6eA_PARP1_prepared.pdb', 
    help="The path to the receptor file. Should be .pdb file.",
)
PARSER.add_argument(
    "--center_x",
    "-x",
    type=float,
    default=-70.76,
    help="x-coordinate for the center of the pocket to be tested by docking. (Angstrom)",
)
PARSER.add_argument(
    "--center_y",
    "-y",
    type=float,
    default=21.82,
    help="y-coordinate for the center of the pocket to be tested by docking. (Angstrom)",
)
PARSER.add_argument(
    "--center_z",
    "-z",
    type=float,
    default=28.33,
    help="z-coordinate for the center of the pocket to be tested by docking. (Angstrom)",
)

PARSER.add_argument(
    "--size_x",
    type=float,
    default=25.0,
    help="dimension of box to dock into in the x-axis (Angstrom)",
)
PARSER.add_argument(
    "--size_y",
    type=float,
    default=20.0,
    help="dimension of box to dock into in the y-axis (Angstrom)",
)
PARSER.add_argument(
    "--size_z",
    type=float,
    default=25.0,
    help="dimension of box to dock into in the z-axis (Angstrom)",
)


# Input/Output directories
PARSER.add_argument(
    "--root_output_folder",
    "-o",
    type=str,
    help="The Path to the folder which all output files will be placed.",
)
PARSER.add_argument(
    "--source_compound_file",
    "-s",
    type=str,
    default='./source_compounds/naphthalene_smiles.smi',
    help="PATH to the file containing the source compounds. It must be \
    tab-delineated .smi file. These ligands will seed the first generation.",
)
PARSER.add_argument(
    "--filter_source_compounds",
    choices=[True, False, "True", "False", "true", "false"],
    default=True,
    help="If True source ligands from source_compound_file will be \
    filter using the user defined filter choices prior to the 1st generation being \
    created. If False, ligands which would fail the ligand filters could seed \
    the 1st generation. Default is True.",
)
PARSER.add_argument(
    "--use_docked_source_compounds",
    choices=[True, False, "True", "False", "true", "false"],
    default=False,
    help="If True source ligands will be docked prior to seeding generation 1. \
    If True and the source_compound file already has docking/fitness metric score \
    in -2 column of .smi file, it will not redock but reuse the scores from \
    the source_compound_file.\
    If True and no fitness metric score in -2 column of .smi file, it will \
    dock each ligand from the source_compound_file and displayed as generation 0.\
    If False, generation 1 will be randomly seeded by the source compounds with \
    no preference and there will be no generation 0. \
    If performing multiple simulations using same source compounds and protein, \
    we recommend running once this and using the generation 0 ranked file as the \
    source_compound_file for future simulations. \
    Default is True.",
)
PARSER.add_argument(
    "--start_a_new_run",
    action="store_true",
    default=False,
    help="If False make a new folder and start a fresh simulation with Generation 0.  \
    If True find the last generation in the root_output_folder and continue to fill.\
    Default is False.",
)



# SmilesMerge Settings
PARSER.add_argument(
    "--max_time_MCS_prescreen",
    type=int,
    default=1,
    help="amount time the pre-screen MCS times out. Time out doesnt prevent \
    mcs matching just takes what it has up to that point",
)
PARSER.add_argument(
    "--max_time_MCS_thorough",
    type=int,
    default=1,
    help="amount time the thorough MCS times out. Time out doesnt prevent \
    mcs matching just takes what it has up to that point",
)
PARSER.add_argument(
    "--min_atom_match_MCS",
    type=int,
    default=4,
    help="Determines the minimum number of atoms in common for a substructurematch. \
    The higher the more restrictive, but the more likely for two ligands not to match",
)
PARSER.add_argument(
    "--protanate_step",
    action="store_true",
    default=False,
    help="Indicates if Smilesmerge uses protanated mols (if true) or deprot \
    (if False) SmilesMerge is 10x faster when deprotanated",
)


# Mutation Settings
PARSER.add_argument(
    "--rxn_library",
    choices=["click_chem_rxns", "robust_rxns", "all_rxns", "Custom"],
    default="all_rxns",
    help="This set of reactions to be used in Mutation. \
    If Custom, one must also provide rxn_file Path and function_group_library path",
)
PARSER.add_argument(
    "--rxn_library_file",
    type=str,
    default="",
    help="This PATH to a Custom json file of SMARTS reactions to use for Mutation. \
    Only provide if using the Custom option for rxn_library.",
)
PARSER.add_argument(
    "--function_group_library",
    type=str,
    default="",
    help="This PATH for a dictionary of functional groups to be used for Mutation. \
    Only provide if using the Custom option for rxn_library.",
)
PARSER.add_argument(
    "--complementary_mol_directory",
    type=str,
    default="",
    help="This PATH to the directory containing all the molecules being used \
    to react with. The directory should contain .smi files contain SMILES of \
    molecules containing the functional group represented by that file. Each file \
    should be named with the same title as the functional groups described in \
    rxn_library_file & function_group_library +.smi \
    All Functional groups specified function_group_library must have its \
    own .smi file. We recommend you filter these dictionaries prior to Autogrow \
    for the Drug-likeliness and size filters you will Run Autogrow with.",
)


# processors and multithread mode
PARSER.add_argument(
    "--number_of_processors",
    "-p",
    type=int,
    metavar="N",
    default=1,
    help="Number of processors to use for parallel calculations. Set to -1 for all available CPUs.",
)
PARSER.add_argument(
    "--multithread_mode",
    default="multithreading",
    choices=["mpi", "multithreading", "serial"],
    help="Determine what style \
    multithreading: mpi, multithreading, or serial. serial will override \
    number_of_processors and force it to be on a single processor.",
)

# Genetic Algorithm Options
PARSER.add_argument(
    "--selector_choice",
    choices=["Roulette_Selector", "Rank_Selector", "Tournament_Selector"],
    default="Roulette_Selector",
    help="This determines whether the fitness criteria are chosen by a Weighted Roulette, \
    Ranked, or Tournament style Selector. The Rank option is a non-redundant selector.\
    Roulette and Tournament chose without replacement and are stoichastic options. \
    Warning do not use Rank_Selector for small runs as there is potential that \
    the number of desired ligands exceed the number of ligands to chose from.",
)
PARSER.add_argument(
    "--tourn_size",
    type=float,
    default=0.1,
    help="If using the Tournament_Selector this determines the size of each \
    tournament. The number of ligands used for each tournament will the \
    tourn_size * the number of considered ligands.",
)

# Seeding next gen and diversity
PARSER.add_argument(
    "--top_mols_to_seed_next_generation_first_generation",
    type=int,
    help="Number of mols that seed next generation, for the first generation.\
    Should be less than number_of_crossovers_first_generation + number_of_mutations_first_generation\
    If not defined it will default to top_mols_to_seed_next_generation",
)
PARSER.add_argument(
    "--top_mols_to_seed_next_generation",
    type=int,
    default=10,
    help="Number of mols that seed next generation, for all generations after the first.\
    Should be less than number_of_crossovers_first_generation \
    + number_of_mutations_first_generation",
)
PARSER.add_argument(
    "--diversity_mols_to_seed_first_generation",
    type=int,
    default=10,
    help="Should be less than number_of_crossovers_first_generation \
    + number_of_mutations_first_generation",
)
PARSER.add_argument(
    "--diversity_seed_depreciation_per_gen",
    type=int,
    default=2,
    help="Each gen diversity_mols_to_seed_first_generation will decrease this amount",
)

# Populations settings
PARSER.add_argument(
    "--num_generations",
    type=int,
    default=10,
    help="The number of generations to be created.",
)
PARSER.add_argument(
    "--number_of_crossovers_first_generation",
    type=int,
    help="The number of ligands which will be created via crossovers in the \
    first generation. If not defined it will default to number_of_crossovers",
)
PARSER.add_argument(
    "--number_of_mutants_first_generation",
    type=int,
    help="The number of ligands which will be created via mutation in \
    the first generation. If not defined it will default to number_of_mutants",
)
PARSER.add_argument(
    "--number_elitism_advance_from_previous_gen_first_generation",
    type=int,
    help="The number of ligands chosen for elitism for the first generation \
    These will advance from the previous generation directly into the next \
    generation.  This is purely advancing based on Docking/Rescore fitness. \
    This does not select for diversity. If not defined it will default to \
    number_elitism_advance_from_previous_gen",
)
PARSER.add_argument(
    "--number_of_crossovers",
    type=int,
    default=10,
    help="The number of ligands which will be created via crossover in each \
    generation besides the first",
)
PARSER.add_argument(
    "--number_of_mutants",
    type=int,
    default=10,
    help="The number of ligands which will be created via mutation in each \
    generation besides the first.",
)
PARSER.add_argument(
    "--number_elitism_advance_from_previous_gen",
    type=int,
    default=10,
    help="The number of ligands chosen for elitism. These will advance from \
    the previous generation directly into the next generation. \
    This is purely advancing based on Docking/Rescore \
    fitness. This does not select for diversity.",
)
PARSER.add_argument(
    "--redock_elite_from_previous_gen",
    choices=[True, False, "True", "False", "true", "false"],
    default=False,
    help="If True than ligands chosen via Elitism (ie advanced from last generation) \
    will be passed through Gypsum and docked again. This provides a better exploration of conformer space \
    but also requires more computation time. If False, advancing ligands are simply carried forward by \
    copying the PDBQT files.",
)

####### FILTER VARIABLES
PARSER.add_argument(
    "--LipinskiStrictFilter",
    action="store_true",
    default=False,
    help="Lipinski filters for orally available drugs following Lipinski rule of fives. \
    Filters by molecular weight, logP and number of hydrogen bond donors and acceptors. \
    Strict implementation means a ligand must pass all requirements.",
)
PARSER.add_argument(
    "--LipinskiLenientFilter",
    action="store_true",
    default=False,
    help="Lipinski filters for orally available drugs following Lipinski rule of fives. \
    Filters by molecular weight, logP and number of hydrogen bond donors and acceptors. \
    Lenient implementation means a ligand may fail all but one requirement and still passes.",
)
PARSER.add_argument(
    "--GhoseFilter",
    action="store_true",
    default=False,
    help="Ghose filters for drug-likeliness; filters by molecular weight,\
    logP and number of atoms.",
)
PARSER.add_argument(
    "--GhoseModifiedFilter",
    action="store_true",
    default=False,
    help="Ghose filters for drug-likeliness; filters by molecular weight,\
    logP and number of atoms. This is the same as the GhoseFilter, but \
    the upper-bound of the molecular weight restrict is loosened from \
    480Da to 500Da. This is intended to be run with Lipinski Filter and \
    to match AutoGrow 3's Ghose Filter.",
)
PARSER.add_argument(
    "--MozziconacciFilter",
    action="store_true",
    default=False,
    help="Mozziconacci filters for drug-likeliness; filters by the number of \
    rotatable bonds, rings, oxygens, and halogens.",
)
PARSER.add_argument(
    "--VandeWaterbeemdFilter",
    action="store_true",
    default=False,
    help="VandeWaterbeemd filters for drug likely to be blood brain barrier permeable. \
    Filters by the number of molecular weight and Polar Sureface Area (PSA).",
)
PARSER.add_argument(
    "--PAINSFilter",
    action="store_true",
    default=False,
    help="PAINS filters against Pan Assay Interference Compounds using \
    substructure a search.",
)
PARSER.add_argument(
    "--NIHFilter",
    action="store_true",
    default=False,
    help="NIH filters against molecules with undersirable functional groups \
    using substructure a search.",
)
PARSER.add_argument(
    "--BRENKFilter",
    action="store_true",
    default=False,
    help="BRENK filter for lead-likeliness, by matching common false positive \
    molecules to the current mol.",
)
PARSER.add_argument(
    "--No_Filters",
    action="store_true",
    default=False,
    help="No filters will be applied to compounds.",
)
PARSER.add_argument(
    "--alternative_filter",
    action="append",
    help="If you want to add Custom filters to the filter child classes \
    Must be a list of lists \
    [[name_filter1, Path/to/name_filter1.py],[name_filter2, Path/to/name_filter2.py]]",
)

# dependency variables
# DOCUMENT THE file conversion for docking inputs
PARSER.add_argument(
    "--conversion_choice",
    choices=["MGLToolsConversion", "ObabelConversion", "Custom"],
    default="MGLToolsConversion",
    help="Determines how .pdb files will be converted \
    to the final format for docking. For Autodock Vina and QuickVina style docking software, \
    files must be in .pdbqt format. MGLToolsConversion: uses MGLTools and is the \
    recommended converter. MGLTools conversion is required for NNScore1/2 rescoring. \
    ObabelConversion: uses commandline obabel. Easier to install but Vina docking has \
    been optimized with MGLTools conversion.",
)
PARSER.add_argument(
    "--custom_conversion_script",
    metavar="custom_conversion_script",
    default="",
    help="The path to a python script for which is used to convert \
    ligands. This is required for custom conversion_choice choices. \
    Must be a list of strings \
    [name_custom_conversion_class, Path/to/name_custom_conversion_class.py]",
)
PARSER.add_argument(
    "--mgltools_directory",
    metavar="mgltools_directory",
    help="Required if using MGLTools conversion option \
    (conversion_choice=MGLToolsConversion) \
    Path may look like: /home/user/MGLTools-1.5.6/",
)
PARSER.add_argument(
    "--mgl_python",
    metavar="mgl_python",
    required=False,
    help="/home/user/MGLTools-1.5.4/bin/pythonsh",
)
PARSER.add_argument(
    "--prepare_ligand4.py",
    metavar="prepare_ligand4.py",
    required=False,
    help="/home/user/MGLTools-1.5.4/MGLToolsPckgs/AutoDockTools/Utilities24/prepare_ligand4.py",
)
PARSER.add_argument(
    "--prepare_receptor4.py",
    metavar="prepare_receptor4.py",
    required=False,
    help="/home/userMGLTools-1.5.4/MGLToolsPckgs/AutoDockTools/Utilities24/prepare_receptor4.py",
)
PARSER.add_argument(
    "--obabel_path",
    help="required if using obabel conversion \
    option (conversion_choice=ObabelConversion).\
    Path may look like PATH/envs/py37/bin/obabel; \
    may be found on Linux by running: which obabel",
)


###################################
######### docking #################
###################################
PARSER.add_argument(
    "--dock_choice",
    metavar="dock_choice",
    default="QuickVina2Docking",
    choices=["VinaDocking", "QuickVina2Docking", "Custom"],
    help="dock_choice assigns which docking software module to use.",
)
PARSER.add_argument(
    "--docking_executable",
    metavar="docking_executable",
    default=None,
    help="path to the docking_executable",
)
PARSER.add_argument(
    "--docking_exhaustiveness",
    metavar="docking_exhaustiveness",
    default=None,
    help="exhaustiveness of the global search (roughly proportional to time. \
    see docking software for settings. Unless specified Autogrow uses the \
    docking softwares default setting. For AutoDock Vina 1.1.2 that is 8",
)
PARSER.add_argument(
    "--docking_num_modes",
    metavar="docking_num_modes",
    default=None,
    help=" maximum number of binding modes to generate in docking. \
    See docking software for settings. Unless specified Autogrow uses the \
    docking softwares default setting. For AutoDock Vina 1.1.2 that is 9",
)
PARSER.add_argument(
    "--docking_timeout_limit",
    type=float,
    default=120,
    help="The maximum amount of time allowed to dock a single ligand into a \
    pocket in seconds. Many factors influence the time required to dock, such as: \
    processor speed, the docking software, rotatable bonds, exhaustiveness docking,\
    and number of docking modes... \
    The default docking_timeout_limit is 120 seconds, which is excess for most \
    docking events using QuickVina2Docking under default settings. If run with \
    more exhaustive settings or with highly flexible ligands, consider increasing \
    docking_timeout_limit to accommodate. Default docking_timeout_limit is 120 seconds",
)
PARSER.add_argument(
    "--custom_docking_script",
    metavar="custom_docking_script",
    default="",
    help="The name and path to a python script for which is used to \
    dock ligands. This is required for Custom docking choices Must be a list of \
    strings [name_custom_conversion_class, Path/to/name_custom_conversion_class.py]",
)

# scoring
PARSER.add_argument(
    "--scoring_choice",
    metavar="scoring_choice",
    choices=["VINA", "NN1", "NN2", "Custom"],
    default="VINA",
    help="The scoring_choice to use to assess the ligands docking fitness. \
    Default is using Vina/QuickVina2 ligand affinity while NN1/NN2 use a Neural Network \
    to assess the docking pose. Custom requires providing a file path for a Custom \
    scoring function. If Custom scoring function, confirm it selects properly, \
    Autogrow is largely set to select for a more negative score.",
)
PARSER.add_argument(
    "--rescore_lig_efficiency",
    action="store_true",
    default=False,
    help="This will divide the final scoring_choice output by the number of \
    non-Hydrogen atoms in the ligand. This adjusted ligand efficiency score will \
    override the scoring_choice value. This is compatible with all scoring_choice options.",
)
PARSER.add_argument(
    "--custom_scoring_script",
    metavar="custom_scoring_script",
    type=str,
    default="",
    help="The path to a python script for which is used to \
    assess the ligands docking fitness. Autogrow is largely set to select for a most \
    negative scores (ie binding affinity the more negative is best). Must be a list of \
    strings [name_custom_conversion_class, Path/to/name_custom_conversion_class.py]",
)

# gypsum # max variance is the number of conformers made per ligand
PARSER.add_argument(
    "--max_variants_per_compound",
    type=int,
    default=3,
    help="number of conformers made per ligand. \
    See Gypsum-DL publication for details",
)
PARSER.add_argument(
    "--gypsum_thoroughness",
    "-t",
    type=int,
    default = 3, 
    help="How widely Gypsum-DL will search for \
    low-energy conformers. Larger values increase \
    run times but can produce better results. \
    See Gypsum-DL publication for details",
)
PARSER.add_argument(
    "--min_ph",
    metavar="MIN",
    type=float,
    default=6.4,
    help="Minimum pH to consider.See Gypsum-DL \
    and Dimorphite-D publication for details.",
)
PARSER.add_argument(
    "--max_ph",
    metavar="MAX",
    type=float,
    default=8.4,
    help="Maximum pH to consider.See Gypsum-DL \
    and Dimorphite-D publication for details.",
)
PARSER.add_argument(
    "--pka_precision",
    metavar="D",
    type=float,
    default=1.0,
    help="Size of pH substructure ranges. See Dimorphite-DL \
    publication for details.",
)
PARSER.add_argument(
    "--gypsum_timeout_limit",
    type=float,
    default=15,
    help="Maximum time gypsum is allowed to run for a given ligand in seconds. \
    On average Gypsum-DL takes on several seconds to run for a given ligand, but \
    factors such as mol size, rotatable bonds, processor speed, and gypsum \
    settings (ie gypsum_thoroughness or max_variants_per_compound) will change \
    how long it takes to run. If increasing gypsum settings it is best to increase \
    the gypsum_timeout_limit. Default gypsum_timeout_limit is 15 seconds",
)

# Reduce files down. This compiles and compresses the files in the PDBs folder
# (contains docking outputs, pdb, pdbqt...). This reduces the data size and
# makes data transfer quicker, but requires running the
# file_concatenation_and_compression.py in the Utility script folder to
# separate these files out for readability.
PARSER.add_argument(
    "--reduce_files_sizes",
    choices=[True, False, "True", "False", "true", "false"],
    default=True,
    help="Run this combines all files in the PDBs folder into a \
    single text file. Useful when data needs to be transferred.",
)

# Make a line plot of the simulation at the end of the run.
PARSER.add_argument(
    "--generate_plot",
    choices=[True, False, "True", "False", "true", "false"],
    default=True,
    help="Make a line plot of the simulation at the end of the run.",
)

# mpi mode pre-Run so there are python cache files without EOF Errors
PARSER.add_argument(
    "--cache_prerun",
    "-c",
    action="store_true",
    help="Run this before running gypsum in mpi-mode.",
)


args_dict = vars(PARSER.parse_args())
from autogrow.user_vars import multiprocess_handling, define_defaults, determine_bash_timeout_vs_gtimeout
# args_dict = define_defaults()


import copy 
INPUTS = copy.deepcopy(args_dict)

for k, v in args_dict.items():
    if v is None:
        del INPUTS[k]

if args_dict["cache_prerun"] is False:
    # load the commandline parameters
    from autogrow.user_vars import load_in_commandline_parameters
    args_dict, printout = load_in_commandline_parameters(INPUTS)



args_dict = multiprocess_handling(args_dict)

timeout_option = determine_bash_timeout_vs_gtimeout()
if timeout_option in  ["timeout", "gtimeout"]:
    args_dict["timeout_vs_gtimeout"] = timeout_option
else:
    raise Exception("Something is very wrong. This OS may not be supported by \
                    Autogrow or you may need to execute through Bash.")


'''
python run.py \
    --filename_of_receptor ./tutorial/PARP/4r6eA_PARP1_prepared.pdb \
    --center_x -70.76 --center_y  21.82 --center_z 28.33 \
    --size_x 25.0 --size_y 16.0 --size_z 25.0 \
    --source_compound_file ./source_compounds/naphthalene_smiles.smi \
    --root_output_folder ./output \
    --number_of_mutants_first_generation 50 \
    --number_of_crossovers_first_generation 50 \
    --number_of_mutants 50 \
    --number_of_crossovers 50 \
    --top_mols_to_seed_next_generation 50 \
    --number_elitism_advance_from_previous_gen 50 \
    --number_elitism_advance_from_previous_gen_first_generation 10 \
    --diversity_mols_to_seed_first_generation 10 \
    --diversity_seed_depreciation_per_gen 10 \
    --num_generations 5 \
    --mgltools_directory ./mgltools_x86_64Linux2_1.5.6/ \
    --number_of_processors -1 \
    --scoring_choice VINA \
    --LipinskiLenientFilter \
    --start_a_new_run \
    --rxn_library click_chem_rxns \
    --selector_choice Rank_Selector \
    --dock_choice VinaDocking \
    --max_variants_per_compound 5 \
    --redock_elite_from_previous_gen False \
    --generate_plot True \
    --reduce_files_sizes True \
    --use_docked_source_compounds True  
'''

import numpy as np
import os, json, pickle, time, sys  
# import torch
# from autogrow.model import Ligand2D

"""
	- docking 
	- reaction (mutation) 
	- common structure (crossover)
	- train policy 
"""

filename_of_receptor = "./tutorial/PARP/4r6eA_PARP1_prepared.pdb"
center = [-70.76, 21.82, 28.33]
box_size = [20.0, 20.0, 20.0]

source_compound_file = args_dict['source_compound_file']
with open(source_compound_file, 'r') as fin:
	lines = fin.readlines() 
	population_list = [line.split()[0] for line in lines]

## TODO1 smiles -> sdf -> pdb -> pdbqt 
import autogrow.operators.convert_files.conversion_to_3d as conversion_to_3d
# conversion_to_3d.convert_smi_to_sdfs_with_gypsum 
# conversion_to_3d.convert_sdf_to_pdbs
# convert_sdf_to_pdbs(vars, gen_folder_path, sdfs_folder_path)
# conversion_to_3d.convert_single_sdf_to_pdb
# convert_ligand_pdb_file_to_pdbqt #### in run_docking_common lig_convert_multithread 

def smiles_to_sdfs(vars, gen_smiles_file, smile_file_directory):
    # conversion_to_3d.convert_smi_to_sdfs_with_gypsum 
    max_variants_per_compound = vars["max_variants_per_compound"]
    gypsum_thoroughness = vars["gypsum_thoroughness"]
    min_ph = vars["min_ph"]
    max_ph = vars["max_ph"]
    pka_precision = vars["pka_precision"]
    gypsum_timeout_limit = vars["gypsum_timeout_limit"]

    # Make a new folder to put gypsum .smi's and json. Name folder gypsum_submission_files.
    folder_path = "{}gypsum_submission_files{}".format(smile_file_directory, os.sep)
    if os.path.exists(folder_path) is False:
        os.makedirs(folder_path)

    # Make Output for Gypsum folder (where .sdf's go)
    gypsum_output_folder_path = "{}3D_SDFs{}".format(smile_file_directory, os.sep)
    if os.path.exists(gypsum_output_folder_path) is False:
        os.makedirs(gypsum_output_folder_path)

    # Make a folder to put the log files into within the 3D_SDFs folder
    gypsum_log_path = "{}log{}".format(gypsum_output_folder_path, os.sep)
    if os.path.exists(gypsum_log_path) is False:
        os.makedirs(gypsum_log_path)

    # Make All of the json files to submit to gypsum
    list_of_gypsum_params = conversion_to_3d.make_smi_and_gyspum_params(
        gen_smiles_file,
        folder_path,
        gypsum_output_folder_path,
        max_variants_per_compound, gypsum_thoroughness,
        min_ph, max_ph, pka_precision, )

    # create a the job_inputs to run gypsum in multithread
    job_input = tuple([(gypsum_log_path, gypsum_params, gypsum_timeout_limit) for gypsum_params in list_of_gypsum_params])

    sys.stdout.flush()
    failed_to_convert = vars["parallelizer"].run(job_input, conversion_to_3d.run_gypsum_multiprocessing)
    sys.stdout.flush()

    ###    fail: return smiles 
    ###    success: return None     
    lig_failed_to_convert = [x for x in failed_to_convert if x is not None]
    lig_failed_to_convert = list(set(lig_failed_to_convert))
    if len(lig_failed_to_convert) > 0:
        print("The Following ligands Failed to convert in Gypsum")
        print("Likely due to a Timeout")
        print(lig_failed_to_convert)
    sys.stdout.flush()
    return gypsum_output_folder_path


from autogrow.docking.execute_docking import pick_run_conversion_class_dict, pick_docking_class_dict, lig_convert_multithread
def pdb_to_pdbqt(vars, pdb_dir):
    ### adapted from run_docking_common
    dock_choice = vars["dock_choice"]
    conversion_choice = vars["conversion_choice"]
    receptor = vars["filename_of_receptor"]

    # Use a temp vars dict so you don't put mpi multiprocess info through itself...
    temp_vars = {}
    for key in list(vars.keys()):
        if key == "parallelizer":
            continue
        temp_vars[key] = vars[key]

    file_conversion_class_object = pick_run_conversion_class_dict(conversion_choice)
    file_conversion_class_object = file_conversion_class_object(temp_vars, receptor, test_boot=False)

    dock_class = pick_docking_class_dict(dock_choice)
    docking_object = dock_class(temp_vars, receptor, file_conversion_class_object, test_boot=False)

    if vars["docking_executable"] is None:
        docking_executable = docking_object.get_docking_executable_file(temp_vars)
        vars["docking_executable"] = docking_executable
    ##### vina or Qvina 

    # Find PDB's
    pdbs_in_folder = docking_object.find_pdb_ligands(pdb_dir)
    print('all pdb file', pdbs_in_folder, pdb_dir)
    job_input_convert_lig = tuple([(docking_object, pdb) for pdb in pdbs_in_folder])

    print("Convert Ligand from PDB to PDBQT format")
    smiles_names_failed_to_convert = vars["parallelizer"].run(job_input_convert_lig, lig_convert_multithread)

    pdbqts_in_folder = docking_object.find_converted_ligands(pdb_dir)
    print('pdbqt file', pdbqts_in_folder)
    return docking_object


gypsum_output_folder_path = smiles_to_sdfs(args_dict, source_compound_file, smile_file_directory='./source_compounds')
conversion_to_3d.convert_sdf_to_pdbs(args_dict, gen_folder_path='./source_compounds', sdfs_folder_path='./source_compounds3D_SDFs')
docking_object = pdb_to_pdbqt(vars = args_dict, pdb_dir = './source_compoundsPDBs/')
### output directory: source_compoundsPDBs 


## TODO2 docking an pdbqt
from autogrow.docking.execute_docking import run_dock_multithread, run_docking_common
import autogrow.docking.scoring.execute_scoring_mol as Scoring
# run_dock 
# dock_ligand 

def docking_pdbqt(vars, docking_object, pdbqt_folder):
    pdbqts_in_folder = docking_object.find_converted_ligands(pdbqt_folder)
    job_input_dock_lig = tuple([tuple([docking_object, pdbqt]) for pdbqt in pdbqts_in_folder])
    smiles_names_failed_to_dock = vars["parallelizer"].run(job_input_dock_lig, run_dock_multithread)

    deleted_smiles_names_list_dock = [x for x in smiles_names_failed_to_dock if x is not None]
    deleted_smiles_names_list_dock = list(set(deleted_smiles_names_list_dock))
    print("THE FOLLOWING LIGANDS WHICH FAILED TO DOCK:", deleted_smiles_names_list_dock)
    print("####################")


    print("#################### save results #####################")
    print("\nBegin Ranking and Saving results")
    smiles_list = Scoring.run_scoring_common(vars, smile_file, folder_with_pdbqts)

    # unweighted_ranked_smile_file = docking_object.rank_and_save_output_smi(
    #     vars,
    #     current_generation_dir,
    #     current_gen_int,
    #     smile_file_new_gen,
    #     deleted_smiles_names_list,
    # )


docking_pdbqt(args_dict, docking_object, './source_compoundsPDBs')
print('docking done')

# ## TODO3 reaction for mutate 
# reaction_list = []
# make_mutants

## TODO4 crossover between 2 ligands 


exit()












def train():
	mutate_ligand_select_policy_net = Ligand2D() 
	mutate_reaction_select_policy_net = Ligand2D()
	crossover_ligand1_policy_net = Ligand2D() 
	crossover_ligand2_policy_net = Ligand2D()

	opt1 = torch.optim.Adam(mutate_ligand_select_policy_net.parameters(), lr=1e-3)
	opt2 = torch.optim.Adam(mutate_reaction_select_policy_net.parameters(), lr=1e-3)
	opt3 = torch.optim.Adam(crossover_ligand1_policy_net.parameters(), lr=1e-3)
	opt4 = torch.optim.Adam(crossover_ligand2_policy_net.parameters(), lr=1e-3)
	return 

	for step in range(n_step): 

		## select protein pocket

		reaction 
		# 1. mutation 
		for i in range(n_mutation):
			## 1.1 select ligand_1 from population_list
			population_list 
			## get 3d ligand 

			## evaluate likelihood 

			## sample the ligand from policy distribution  
			mutated_smiles, mutated_smiles_likelihood = policy_net.sample() 
			### 1.2 select reaction from reaction_list 
			reaction_list 
			reaction, mutated_reaction_likelihood = policy_net.sample() 
			new_smiles = mutation(mutated_smiles, reaction)

			### reward 
			score = oracle(new_smiles)
			reward = score 



		# crossover  
		for i in range(n_crossover):
			## select ligand_1 
			crossover_ligand_1, crossover_ligand1_likelihood = policy_net.sample() 
			## select ligand_2 conditioned on ligand_1  
			crossover_ligand_2, crossover_ligand2_likelihood = policy_net.sample()
			new_smiles = crossover(ligand_1, ligand_2)

			### reward 	
			score = oracle(new_smiles)
			reward = score

		#### add Experience


		## optimization 
		optimizer.zero_grad()
		loss.backward()
		optimizer.step()

		##### logging 




if __name__ == '__main__':
	train() 



"""
TODO 

Experience 


"""