Journal of Computer-Aided Molecular Design

, Volume 13, Issue 1, pp 35–49 | Cite as

Methodological developments and strategies for a fast flexible superposition of drug-size molecules

  • Gerhard Klebe
  • Thomas Mietzner
  • Frank Weber


An alternative to experimental high through-put screening is the virtual screening of compound libraries on the computer. In absence of a detailed structure of the receptor protein, candidate molecules are compared with a known reference by mutually superimposing their skeletons and scoring their similarity. Since molecular shape highly depends on the adopted conformation, an efficient conformational screening is performed using a knowledge-based approach. A comprehensive torsion library has been compiled from crystal data stored in the Cambridge Structural Database. For molecular comparison a strategy is followed considering shape associated physicochemical properties in space such as steric occupancy, electrostatics, lipophilicity and potential hydrogen-bonding. Molecular shape is approximated by a set of Gaussian functions not necessarily located at the atomic positions. The superposition is performed in two steps: first by a global alignment search operating on multiple rigid conformations and then by conformationally relaxing the best scored hits of the global search. A normalized similarity scoring is used to allow for a comparison of molecules with rather different shape and size. The approach has been implemented on a cluster of parallel processors. As a case study, the search for ligands binding to the dopamine receptor is given.

knowledge-based conformational search molecular similarity molecular superposition torsional library virtual screening 


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Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • Gerhard Klebe
    • 1
  • Thomas Mietzner
    • 1
  • Frank Weber
    • 1
  1. 1.BASF AG, HauptlaboratoriumLudwigshafenGermany

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