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A genetic algorithm for flexible molecular overlay and pharmacophore elucidation

Journal of Computer-Aided Molecular Design volume 9, pages 532–549 (1995)Cite this article

Summary

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.

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Author notes

  1. Robert C. Glen

    Present address: Tripos Associates Inc., 63144, St. Louis, MO, U.S.A.

Authors and Affiliations

  1. Department of Information Studies, University of Sheffield, Western Bank, S10 2TN, Sheffield, U.K.

    Gareth Jones & Peter Willett

  2. Krebs Institute for Biomolecular Research, University of Sheffield, Western Bank, S10 2TN, Sheffield, U.K.

    Gareth Jones

  3. Department of Physical Sciences, Wellcome Research Laboratories, BR3 3BS, Beckenham, Kent, U.K.

    Robert C. Glen

Authors
  1. Gareth Jones
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  2. Peter Willett
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  3. Robert C. Glen
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Jones, G., Willett, P. & Glen, R.C. A genetic algorithm for flexible molecular overlay and pharmacophore elucidation. J Computer-Aided Mol Des 9, 532–549 (1995). https://doi.org/10.1007/BF00124324

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  • DOI: https://doi.org/10.1007/BF00124324

Keywords

  • Genetic algorithm
  • Flexible conformational search
  • Superimposition