A genetic algorithm for flexible molecular overlay and pharmacophore elucidation

J Comput Aided Mol Des. 1995 Dec;9(6):532-49. doi: 10.1007/BF00124324.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms*
  • Angiotensin Receptor Antagonists
  • Benzodiazepines / chemistry
  • Binding Sites
  • Carrier Proteins / chemistry
  • DNA-Binding Proteins / chemistry
  • Dopamine Agonists / chemistry
  • Drug Design*
  • Enkephalin, Leucine / chemistry
  • Heat-Shock Proteins / chemistry
  • Hydrogen Bonding
  • Ligands
  • Models, Genetic*
  • Models, Molecular
  • Molecular Structure
  • Morphine / chemistry
  • Serotonin Antagonists / chemistry
  • Software
  • Tacrolimus Binding Proteins
  • Thermodynamics


  • Angiotensin Receptor Antagonists
  • Carrier Proteins
  • DNA-Binding Proteins
  • Dopamine Agonists
  • Heat-Shock Proteins
  • Ligands
  • Serotonin Antagonists
  • Benzodiazepines
  • Enkephalin, Leucine
  • Morphine
  • Tacrolimus Binding Proteins