title: 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.
authors.affiliation: Department of Information Studies, University of Sheffield, Western Bank, UK.
authors.forename: G
authors.initials: G
authors.lastname: Jones
authors.forename: P
authors.initials: P
authors.lastname: Willett
authors.forename: R C
authors.initials: RC
authors.lastname: Glen
mesh_terms: D000465:Algorithms; D057911:Angiotensin Receptor Antagonists; D001569:Benzodiazepines / Q000737:chemistry; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry; D018491:Dopamine Agonists / Q000737:chemistry; D015195:Drug Design; D004743:Enkephalin, Leucine / Q000737:chemistry; D006360:Heat-Shock Proteins / Q000737:chemistry; D006860:Hydrogen Bonding; D008024:Ligands; D008957:Models, Genetic; D008958:Models, Molecular; D015394:Molecular Structure; D009020:Morphine / Q000737:chemistry; D012702:Serotonin Antagonists / Q000737:chemistry; D012984:Software; D022021:Tacrolimus Binding Proteins; D013816:Thermodynamics
chemical_list: D057911:Angiotensin Receptor Antagonists; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D018491:Dopamine Agonists; D006360:Heat-Shock Proteins; D008024:Ligands; D012702:Serotonin Antagonists; D001569:Benzodiazepines; D004743:Enkephalin, Leucine; D009020:Morphine; D022021:Tacrolimus Binding Proteins