Journal of Computer-Aided Molecular Design

, Volume 12, Issue 6, pp 563–572 | Cite as

Do active site conformations of small ligands correspond to low free-energy solution structures?

  • Michal Vieth
  • Jonathan D. Hirst
  • Charles L. BrooksIII


We compare the low free energy structures of ten small, polar ligands in solution to their conformations in their respective receptor active sites. The solution conformations are generated by a systematic search and the free energies of representative structures are computed with a continuum solvation model. Based on the values of torsion angles, we find little similarity between low energy solution structures of small ligands and their active site conformations. However, in nine out of ten cases, the positions of 'anchor points' (key atoms responsible for tight binding) in the lowest energy solution structures are very similar to the positions of these atoms in the active site conformations. A metric that more closely captures the essentials of binding supports the basic premise underlying pharmacophore mapping, namely that active site conformations of small flexible ligands correspond to their low energy structures in solution. This work supports the efforts of building pharmacophore models based on the information present in solution structures of small isolated ligands.

anchor points conformational search ligand binding 


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Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Michal Vieth
    • 1
  • Jonathan D. Hirst
    • 1
  • Charles L. BrooksIII
    • 1
  1. 1.Department of Molecular BiologyThe Scripps Research InstituteLa JollaU.S.A. Current address: Department of Computational Chemistry and Macromolecular Structure Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46032, U.S.A

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