A genetic algorithm for flexible molecular overlay and pharmacophore elucidation

Abstract

A genetic algorithm (GA) has been developed for the superimposition of sets of flexible molecules. Molecules are represented by a chromosome that encodes angles of rotation about flexible bonds and mappings between hydrogen-bond donor proton, acceptor lone pair and ring centre features in pairs of molecules. The molecule with the smallest number of features in the data set is used as a template, onto which the remaining molecules are fitted with the objective of maximising structural equivalences. The fitness function of the GA is a weighted combination of: (i) the number and the similarity of the features that have been overlaid in this way; (ii) the volume integral of the overlay; and (iii) the van der Waals energy of the molecular conformations defined by the torsion angles encoded in the chromosomes. The algorithm has been applied to a number of pharmacophore elucidation problems, i.e., angiotensin II receptor antagonists, Leu-enkephalin and a hybrid morphine molecule, 5-HT1D agonists, benzodiazepine receptor ligands, 5-HT3 antagonists, dopamine D2 antagonists, dopamine reuptake blockers and FKBP12 ligands. The resulting pharmacophores are generated rapidly and are in good agreement with those derived from alternative means.

New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells

“…5PNT [63] and 1XWW [64] were selected as structures for human LMW-PTP IF1 and IF2, respectively. The selected protein structures were processed with CCDCs software GOLD version 5 [65] for docking experiments. After docking, structures were minimized in the binding site using LigandScout's [66] MMFF94 implementation, and prioritized using a 3D pharmacophore model that explains the most plausible docking poses.…”

Generation of multiple pharmacophore hypotheses using multiobjective optimisation techniques

“…Once an alignment has been generated, the energy, volume integral and feature scores are calculated as in GASP [9]. The energy score is the mean internal van der Waals energy of the molecules.…”

“…This is the approach taken in GASP [9] which is based on a genetic algorithm that aims to optimise conformation simultaneously with the goodness of the alignment. Methods that vary conformation on-the-fly typically generate a single solution that represents one possible hypothesis, even though several might exist.…”

Chemoinformatics at the University of Sheffield 2002–2014

“…[64] GASP was developed later in collaboration with the Wellcome Research Laboratories, with the program subsequently being distributed by Certara (previously Tripos Inc.) [65] and DISCO, on a test set derived from X-ray crystal structures of protein-ligand complexes. [66] Five proteins were selected that each had crystal structures with different ligands bound.…”