Volume 2 Supplement 1

5th German Conference on Cheminformatics: 23. CIC-Workshop

Open Access

High throughput in-silico screening against flexible protein receptors

  • Horacio Pérez-Sánchez1,
  • Bernhard Fischer1,
  • Daria Kokh2,
  • Holger Merlitz1 and
  • Wolfgang Wenzel1
Journal of Cheminformatics20102(Suppl 1):P23

https://doi.org/10.1186/1758-2946-2-S1-P23

Published: 04 May 2010

Based on the stochastic tunneling method (STUN) [1] we have developed FlexScreen [2], a novel strategy for high-throughput in-silico screening of large ligand databases. Each ligand of the database is docked against the receptor using an all-atom representation of both ligand and receptor. The ligands with the best evaluated affinity are selected as lead candidates for drug development. Using the thymidine kinase inhibitors as a prototypical example we documented [3] the shortcomings of rigid receptor screens in a realistic system. We demonstrate a gain in both overall binding energy and overall rank of the known substrates when two screens with a rigid and flexible (up to 15 sidechain dihedral angles) receptor are compared. We note that the STUN suffers only a comparatively small loss of efficiency when an increasing number of receptor degrees of freedom is considered. FlexScreen thus offers a viable compromise [4] between docking flexibility and computational efficiency to perform fully automated database screens on hundreds of thousands of ligands. We also investigate enrichment rates [5] of rigid, soft and flexible receptor models [6] for 12 diverse receptors using libraries containing up to 13000 molecules. A flexible sidechain model with flexible dihedral angles for up to 12 aminoacids increased both binding propensity and enrichment rates: EF_1 values increased by 35% on average with respect to rigid-docking (3-8 flexible sidechains). This methodology will be soon available for the Cell processor and Pipeline Pilot.

Authors’ Affiliations

(1)
Institut für Nanotechnologie, Forschungszentrum Karlsruhe
(2)

References

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Copyright

© Horacio et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd.