Chemical structure generation without GPU #chemoinformatics #STONED #rdkit

Generative model is very hot not only in computer vision, natural language processing but also chemoinformatics.

As you know, recent version of deep learning based compound generator works very well but it is required huge computer resources for building the model. And also SMILES based approach sometime generates invalid molecules.

Recently I read very interesting article reported Alan Aspuru-Guzik who is the pioneer of chemical VAE. You can read the article from chemRxiv.

Beyond Generative Models: Superfast Traversal, Optimization, Novelty,
Exploration and Discovery (STONED) Algorithm for Molecules using

As the name describes that STONED uses SELFIES which is new compound representation method which is developed by their group. SELFIES can be install via pip. Just type $pip install selfies.

SELFIES means Self-Referencing Embedded Strings.

So it is a good tool for compound representation.

There are three key methods in STONED, 1) reorder string (randomize SMILES), 2) convert to SELFIES 3) perform random mutations which are addition, deletion and replacement. By using this mutation method, deep learning is not required for compound generation.

Rediscovery with Genetic Algorithm is the one of interesting topic for me.

Rediscovery means that generates target molecule from randomized strings. Fortunately all code is disclosed on github.

So it is easy to run STONED on your PC.

$ git clone
$ cd stoned-selfies

STONED requires selfies, rdkit and numpy. If these packages are available on your PC, STONED will run without error.

I modified to more general. Put out the configuration as yml. My code (modified version) is below.
Created on Sat May 23 18:17:31 2020

    celebx       = 'CC1=CC=C(C=C1)C2=CC(=NN2C3=CC=C(C=C3)S(=O)(=O)N)C(F)(F)F' 
    tiotixene    = 'CN1CCN(CC1)CCC=C2C3=CC=CC=C3SC4=C2C=C(C=C4)S(=O)(=O)N(C)C'
    Troglitazone = 'CC1=C(C2=C(CCC(O2)(C)COC3=CC=C(C=C3)CC4C(=O)NC(=O)S4)C(=C1O)C)C'

@author: akshat
import selfies
import numpy as np 
import random
from rdkit.Chem import MolFromSmiles as smi2mol
from rdkit.Chem import MolToSmiles as mol2smi
from rdkit import Chem
from rdkit.Chem import AllChem
from rdkit.DataStructs.cDataStructs import TanimotoSimilarity
from selfies import encoder, decoder 
from rdkit import RDLogger
import yaml

def get_ECFP4(mol):
    ''' Return rdkit ECFP4 fingerprint object for mol

    mol (rdkit.Chem.rdchem.Mol) : RdKit mol object  

    rdkit ECFP4 fingerprint object for mol
    return AllChem.GetMorganFingerprint(mol, 2)

def sanitize_smiles(smi):
    '''Return a canonical smile representation of smi
    smi (string) : smile string to be canonicalized 
    mol (rdkit.Chem.rdchem.Mol) : RdKit mol object                          (None if invalid smile string smi)
    smi_canon (string)          : Canonicalized smile representation of smi (None if invalid smile string smi)
    conversion_successful (bool): True/False to indicate if conversion was  successful 
        mol = smi2mol(smi, sanitize=True)
        smi_canon = mol2smi(mol, isomericSmiles=False, canonical=True)
        return (mol, smi_canon, True)
        return (None, None, False)

def mutate_selfie(selfie, max_molecules_len, write_fail_cases=False):
    '''Return a mutated selfie string (only one mutation on slefie is performed)
    Mutations are done until a valid molecule is obtained 
    Rules of mutation: With a 50% propbabily, either: 
        1. Add a random SELFIE character in the string
        2. Replace a random SELFIE character with another
    selfie            (string)  : SELFIE string to be mutated 
    max_molecules_len (int)     : Mutations of SELFIE string are allowed up to this length
    write_fail_cases  (bool)    : If true, failed mutations are recorded in "selfie_failure_cases.txt"
    selfie_mutated    (string)  : Mutated SELFIE string
    smiles_canon      (string)  : canonical smile of mutated SELFIE string
    fail_counter = 0
    chars_selfie = get_selfie_chars(selfie)
    while not valid:
        fail_counter += 1
        alphabet = list(selfies.get_semantic_robust_alphabet()) # 34 SELFIE characters 

        choice_ls = [1, 2] # 1=Insert; 2=Replace; 3=Delete
        random_choice = np.random.choice(choice_ls, 1)[0]
        # Insert a character in a Random Location
        if random_choice == 1: 
            random_index = np.random.randint(len(chars_selfie)+1)
            random_character = np.random.choice(alphabet, size=1)[0]
            selfie_mutated_chars = chars_selfie[:random_index] + [random_character] + chars_selfie[random_index:]

        # Replace a random character 
        elif random_choice == 2:                         
            random_index = np.random.randint(len(chars_selfie))
            random_character = np.random.choice(alphabet, size=1)[0]
            if random_index == 0:
                selfie_mutated_chars = [random_character] + chars_selfie[random_index+1:]
                selfie_mutated_chars = chars_selfie[:random_index] + [random_character] + chars_selfie[random_index+1:]
        # Delete a random character
        elif random_choice == 3: 
            random_index = np.random.randint(len(chars_selfie))
            if random_index == 0:
                selfie_mutated_chars = chars_selfie[random_index+1:]
                selfie_mutated_chars = chars_selfie[:random_index] + chars_selfie[random_index+1:]
            raise Exception('Invalid Operation trying to be performed')

        selfie_mutated = "".join(x for x in selfie_mutated_chars)
        sf = "".join(x for x in chars_selfie)
            smiles = decoder(selfie_mutated)
            mol, smiles_canon, done = sanitize_smiles(smiles)
            if len(selfie_mutated_chars) > max_molecules_len or smiles_canon=="":
                done = False
            if done:
                valid = True
                valid = False
            if fail_counter > 1 and write_fail_cases == True:
                f = open("selfie_failure_cases.txt", "a+")
                f.write('Tried to mutate SELFIE: '+str(sf)+' To Obtain: '+str(selfie_mutated) + '\n')
    return (selfie_mutated, smiles_canon)

def get_selfie_chars(selfie):
    '''Obtain a list of all selfie characters in string selfie
    selfie (string) : A selfie string - representing a molecule 
    >>> get_selfie_chars('[C][=C][C][=C][C][=C][Ring1][Branch1_1]')
    ['[C]', '[=C]', '[C]', '[=C]', '[C]', '[=C]', '[Ring1]', '[Branch1_1]']
    chars_selfie: list of selfie characters present in molecule selfie
    chars_selfie = [] # A list of all SELFIE sybols from string selfie
    while selfie != '':
        chars_selfie.append(selfie[selfie.find('['): selfie.find(']')+1])
        selfie = selfie[selfie.find(']')+1:]
    return chars_selfie

def get_reward(selfie_A_chars, selfie_B_chars): 
    '''Return the levenshtein similarity between the selfies characters in 'selfie_A_chars' & 'selfie_B_chars'

    selfie_A_chars (list)  : list of characters of a single SELFIES
    selfie_B_chars (list)  : list of characters of a single SELFIES
    reward (int): Levenshtein similarity between the two SELFIES
    reward = 0
    iter_num = max(len(selfie_A_chars), len(selfie_B_chars)) # Larger of the selfie chars to iterate over 

    for i in range(iter_num): 
        if i+1 > len(selfie_A_chars) or i+1 > len(selfie_B_chars): 
            return reward
        if selfie_A_chars[i] == selfie_B_chars[i]: 
            reward += 1
    return reward

# Executable code for EXPERIMENT C (Three different choices): 
# read params from yaml

cfg = yaml.load(open('ga_conf.yml', 'r'), yaml.SafeLoader)
N                  = cfg['params']['N']  # Number of runs
simlr_path_collect = cfg['params']['simlr_path_collect']
svg_file_name      = cfg['params']['svg_file_name']
starting_mol_name  = cfg['params']['starting_mol_name']
data_file_name     = cfg['params']['data_file_name']
starting_smile     = cfg['params']['starting_smile']
show_gen_out       = cfg['params']['show_gen_out']

len_random_struct  = len(get_selfie_chars(encoder(starting_smile))) # Length of the starting SELFIE structure

for i in range(N): 
    print('Run number: ', i)
    with open(data_file_name, 'a') as myfile:
        myfile.write('RUN {} \n'.format(i))
    # celebx = 'CC1=CC=C(C=C1)C2=CC(=NN2C3=CC=C(C=C3)S(=O)(=O)N)C(F)(F)F' 
    starting_selfie = encoder(starting_smile)
    starting_selfie_chars = get_selfie_chars(starting_selfie)
    max_molecules_len = len(starting_selfie_chars)

    # Random selfie initiation: 
    alphabet = list(selfies.get_semantic_robust_alphabet()) # 34 SELFIE characters 
    selfie = ''
    for i in range(random.randint(1, len_random_struct)): # max_molecules_len = max random selfie string length 
        selfie = selfie + np.random.choice(alphabet, size=1)[0]
    starting_selfie = [selfie]
    print('Starting SELFIE: ', starting_selfie)
    generation_size = 500
    num_generations = 10000
    save_best = []
    simlr_path = []
    reward_path = []
    # Initial set of molecules 
    population = np.random.choice(starting_selfie, size=500).tolist() # All molecules are in SELFIES representation
    for gen_ in range(num_generations): 
        # Calculate fitness for all of them 
        fitness = [get_reward(starting_selfie_chars, get_selfie_chars(x)) for x in population]
        fitness = [float(x)/float(max_molecules_len) for x in fitness] # Between 0 and 1 

        # Keep the best member & mutate the rest 
        #    Step 1: Keep the best molecule
        best_idx = np.argmax(fitness)
        best_selfie = population[best_idx]
        # Diplay some Outputs: 
        if show_gen_out:
            print('Generation: {}/{}'.format(gen_, num_generations))
            print('    Top fitness: ', fitness[best_idx])
            print('    Top SELFIE: ', best_selfie)
        with open(data_file_name, 'a') as myfile:
            myfile.write('    SELFIE: {} FITNESS: {} \n'.format(best_selfie, fitness[best_idx]))

        #    Maybe also print the tanimoto score: 
        mol = Chem.MolFromSmiles(decoder(best_selfie))
        target = Chem.MolFromSmiles(starting_smile)
        fp_mol = get_ECFP4(mol)
        fp_target = get_ECFP4(target)
        score = TanimotoSimilarity(fp_mol, fp_target)
        #    Step 2: Get mutated selfies 
        new_population = []
        for i in range(generation_size-1): 
            # selfie_mutated, _ = mutate_selfie(best_selfie, max_molecules_len, write_fail_cases=True)
            selfie_mutated, _ = mutate_selfie(best_selfie, len_random_struct, write_fail_cases=True) # 100 == max_mol_len allowen in mutation
        # Define new population for the next generation 
        population = new_population[:]
        if score >= 1: 
            print('Limit reached')

import matplotlib.pyplot as plt
x = [i+1 for i in range(max([len(x) for x in simlr_path_collect]))]'classic')
plt.plot(x, [1.2 for _ in range(len(x))], marker='', color='white', linewidth=4) # axis line
plt.plot(x, [1 for _ in range(len(x))], '--', color='orange', linewidth=2.5, label='Rediscovery') # Highlight line

colors =
profiles = 20
color_shift = 0.4
color_values = [ni/profiles + color_shift for ni in range(profiles)]
for ni in range(len(color_values)):
    if color_values[ni] < 0.2:
        color_values[ni] -= 1
cm = [colors(x) for x in color_values]

for i,simlr_path in enumerate(simlr_path_collect): 
    plt.plot([i+1 for i in range(len(simlr_path))], simlr_path, marker='', color=cm[i], linewidth=2.5, alpha=0.5)
plt.title('Rediscovering '+starting_mol_name, fontsize=20, fontweight=0, color='black', loc='left')

plt.ylabel('ECPF4 Similarity')
plt.savefig('Celecoxib_run.png', dpi=196, bbox_inches='tight')
  N                  : 20  # Number of runs
  simlr_path_collect : []
  svg_file_name      : 'Troglitazone_run.svg'
  starting_mol_name  : 'Troglitazone'
  data_file_name     : '20_runs_data_Troglitazone.txt'
  starting_smile     : 'CC1=C(C2=C(CCC(O2)(C)COC3=CC=C(C=C3)CC4C(=O)NC(=O)S4)C(=C1O)C)C'
  show_gen_out       : False

To generate molecule with above config file, just type ‘python

After running the code, I could get image and compounds as selfies in txt file.

OK, let’s check it. Image file is below. After 50 generation, highly similar compounds are generated.

Next, I check structures which are generated STONED.

Sorry, something went wrong. Reload?
Sorry, we cannot display this file.
Sorry, this file is invalid so it cannot be displayed.

As the notebook shows that after running several epochs, target similar compounds are generated. In the original repo some very useful examples are available.

It took short time to conduct GA_based compound generation and it is important that only target molecule is required to run the process.

In summary STONED seems very robust, works fast and doesn’t require huge training data but generates many diverse molecules.

If you have an interest the code, please read original article and check the code.


Published by iwatobipen

I'm medicinal chemist in mid size of pharmaceutical company. I love chemoinfo, cording, organic synthesis, my family.

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: