Journal of Computer-Aided Molecular Design

, Volume 8, Issue 6, pp 751–778

Different approaches toward an automatic structural alignment of drug molecules: Applications to sterol mimics, thrombin and thermolysin inhibitors

  • Gerhard Klebe
  • Thomas Mietzner
  • Frank Weber
Research Papers

DOI: 10.1007/BF00124019

Cite this article as:
Klebe, G., Mietzner, T. & Weber, F. J Computer-Aided Mol Des (1994) 8: 751. doi:10.1007/BF00124019

Summary

A relative comparison of the binding properties of different drug molecules requires their mutual superposition with respect to various alignment criteria. In order to validate the results of different alignment methods, the crystallographically observed binding geometries of ligands in the pocket of a common protein receptor have been used. The alignment function in the program SEAL that calculates the mutual superposition of molecules has been optimized with respect to these references. Across the reference data set, alignments could be produced that show mean rms deviations of approximately 1 Å compared to the experimental situation. For structures with obvious skeletal similarities a multiple-flexible fit, linking common pharmacophoric groups by virtual springs, has been incorporated into the molecular mechanics program MOMO. In order to combine conformational searching with comparative alignments, the optimized SEAL approach has been applied to sets of conformers generated by MIMUMBA, a program for conformational analysis. Multiple-flexible fits have been calculated for inhibitors of ergosterol biosynthesis. Sets of different thrombin and thermolysin inhibitors have been conformationally analyzed and subsequently aligned by a combined MIMUMBA/SEAL approach. Since for these examples crystallographic data on their mutual alignment are available, an objective assessment of the computed results could be performed. Among the generated conformers, one geometry could be selected for the thrombin and thermolysin inhibitors that approached reasonably well the experimentally observed alignment.

Key words

Structural alignmentMolecular flexibilityMolecular similaritySterol mimicsThrombin and thermolysin inhibitors

Copyright information

© ESCOM Science Publishers B.V 1994

Authors and Affiliations

  • Gerhard Klebe
    • 1
  • Thomas Mietzner
    • 1
  • Frank Weber
    • 1
  1. 1.Main LaboratoryBASF AGLudwigshafenGermany