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3D pharmacophore signatures and fingerprints
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README.md

Pmapper - 3D pharmacophore signatures and fingerprints

Pmapper is a Python module to generate 3D pharmacophore signatures and fingerprints. Signatures uniquely encode 3D pharmacophores with hashes suitable for fast identification of identical pharmacophores.

Dependency

rdkit >= 2017.09
networkx >= 1.11

Examples

Load modules

from rdkit import Chem
from rdkit.Chem import AllChem, ChemicalFeatures
from pharmacophore import Pharmacophore as P, read_smarts_feature_file, load_multi_conf_mol
from pprint import pprint

Create pharmacophore from a single comformer using feature definition from SMARTS file

# load a molecule from SMILES and generate 3D coordinates
mol = Chem.MolFromSmiles('C1CC(=O)NC(=O)C1N2C(=O)C3=CC=CC=C3C2=O')  # talidomide
mol = Chem.AddHs(mol)
AllChem.EmbedMolecule(mol, randomSeed=42)

# load pharmacophore feature definitions from SMARTS file
smarts = read_smarts_feature_file('smarts_features.txt')

# create pharmacophore
p = P()
p.load_from_smarts(mol, smarts)

Get 3D pharmacophore signature

# get 3D pharmacophore signature
sig = p.get_signature_md5()
print(sig)

Output:

f2e16f52f6f6ca6e97fc5844bfd35d36

Get 3D pharmacophore signature with non-zero tolerance

sig = p.get_signature_md5(tol=5)
print(sig)

Output:

fb535302db2e5d624aa979b6e8dfbdf2

Create pharmacophore from a single comformer using RDKit feature factory

# load pharmacophore using RDKit factory and get 3D pharmacophore signature
factory = ChemicalFeatures.BuildFeatureFactory('smarts_features.fdef')

p.load_from_feature_factory(mol, factory)
sig = p.get_signature_md5()
print(sig)

Output:

f2e16f52f6f6ca6e97fc5844bfd35d36

Create pharmacophores for a multiple conformer compound

# create multiple conformer molecule
AllChem.EmbedMultipleConfs(mol, numConfs=10, randomSeed=1024)

ps = load_multi_conf_mol(mol, smarts_features=smarts)

sig = [p.get_signature_md5() for p in ps]

pprint(sorted(sig))  # identical signatures occur

Output:

['13d168458ab1f251157f2422efcce312',
 '13d168458ab1f251157f2422efcce312',
 '182a4cfa756fe8b7f736a7f7ac0e8e0a',
 '182a4cfa756fe8b7f736a7f7ac0e8e0a',
 '4234e9d249874a5009f1e312dd885d80',
 'ab273dd083c4f2e3424ba917b121b846',
 'b6ec58553d2984bd398b4520bd1545cc',
 'bfc43365b2657d08b6bb888e4d8ec71b',
 'f5ca8e406dae31182e2b06fde7452b75',
 'fc4a85e818fc0b3f034a7af42fa5ca69']

Generate 3D pharmacophore fingerprint

# generate 3D pharmacophore fingerprint which takes into account stereoconfiguration
b = p.get_fp(min_features=4, max_features=4)   # set of activated bits
print(b)

Output (a set of activated bit numbers):

{1922, 1795, 779, 1040, 528, 920, 154, 1437, 287, 1313, 1447, 1961, 941, 690, 1203, 65, 1346, 709, 1486, 1366, 2006, 1750, 1016, 346, 603, 1116, 354, 995, 228, 2024, 1900, 1524, 888, 2043}

Change settings:

b = p.get_fp(min_features=4, max_features=4, nbits=1024, activate_bits=2)
print(b)

Output (a set of activated bit numbers):

{897, 514, 259, 389, 520, 264, 143, 16, 529, 656, 787, 660, 24, 285, 157, 32, 673, 550, 683, 173, 301, 558, 45, 945, 177, 692, 950, 443, 444, 61, 960, 961, 448, 321, 709, 197, 587, 460, 77, 718, 720, 80, 339, 596, 723, 470, 980, 345, 601, 476, 354, 614, 743, 1003, 875, 494, 367, 497, 114, 1012, 244, 630, 377, 762, 507, 508, 1021}

Save/load pharmacophore

p.save_to_pma('filename.pma')

Output is a text file having json format.

p = P()
p.load_from_pma('filename.pma')

Support LigandScout pml-files

LigandScout models saved as pml-files can be read using p.load_ls_model. Also a pharmacophore can be stored in this format in order to export to LigandScout (p.save_ls_model).

Speed tests

Generation of pharmacopohre signatures (hashes) is a CPU-bound task. The computation speed depends on the number of features in pharmacophores.
Tests were run on 500 compounds (a random subset from Drugbank). Up to 50 conformers were generated for each compound. Up to 100 pharmacophores having a particular number of features were chosen randomly from the whole number of 25000 pharmacophores to generate pharmacophore signatures.
Laptop configuration:

  • Intel(R) Core(TM) i7-5500U CPU @ 2.40GHz
  • 12 GB RAM
  • calculation was run in 1 thread (the module is thread safe and calculations can be parallelized)
pharmacophore generation: 19.21 s
total number of pharmacophores: 25000

pharmacophore hash generation:
50 pharmacophores having 2 features: 0.00 s; time per pharmacophore: 0.00000 s
100 pharmacophores having 3 features: 0.01 s; time per pharmacophore: 0.00010 s
100 pharmacophores having 4 features: 0.01 s; time per pharmacophore: 0.00010 s
100 pharmacophores having 5 features: 0.04 s; time per pharmacophore: 0.00040 s
100 pharmacophores having 6 features: 0.12 s; time per pharmacophore: 0.00120 s
100 pharmacophores having 7 features: 0.24 s; time per pharmacophore: 0.00240 s
100 pharmacophores having 8 features: 0.51 s; time per pharmacophore: 0.00510 s
100 pharmacophores having 9 features: 0.94 s; time per pharmacophore: 0.00940 s
100 pharmacophores having 10 features: 1.86 s; time per pharmacophore: 0.01860 s
100 pharmacophores having 11 features: 3.02 s; time per pharmacophore: 0.03020 s
100 pharmacophores having 12 features: 4.17 s; time per pharmacophore: 0.04170 s
100 pharmacophores having 13 features: 7.04 s; time per pharmacophore: 0.07040 s
100 pharmacophores having 14 features: 9.29 s; time per pharmacophore: 0.09290 s
100 pharmacophores having 15 features: 12.94 s; time per pharmacophore: 0.12940 s
100 pharmacophores having 16 features: 17.79 s; time per pharmacophore: 0.17790 s
100 pharmacophores having 17 features: 23.58 s; time per pharmacophore: 0.23580 s
100 pharmacophores having 18 features: 33.83 s; time per pharmacophore: 0.33830 s
100 pharmacophores having 19 features: 40.43 s; time per pharmacophore: 0.40430 s
100 pharmacophores having 20 features: 58.30 s; time per pharmacophore: 0.58300 s

Citation

Ligand-Based Pharmacophore Modeling Using Novel 3D Pharmacophore Signatures
Alina Kutlushina, Aigul Khakimova, Timur Madzhidov, Pavel Polishchuk
Molecules 2018, 23(12), 3094
https://doi.org/10.3390/molecules23123094

License

BSD-3 clause

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