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Logo of jcheminfoJournal of Cheminformatics
 
J Cheminform. 2010; 2(Suppl 1): P23.
Published online 2010 May 4. doi:  10.1186/1758-2946-2-S1-P23
PMCID: PMC2867156

High throughput in-silico screening against flexible protein receptors

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.

References

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  • Merlitz H, Burghardt B, Wenzel W. Application of the stochastic tunneling method to high throughput database screening. Chemical Physics Letters. 2003;370(1-2):68–73. doi: 10.1016/S0009-2614(02)02012-2. [Cross Ref]
  • Merlitz H, Burghardt B, Wenzel W. Impact of receptor conformation on in silico screening performance. Chemical Physics Letters. 2004;390(4-6):500–505. doi: 10.1016/j.cplett.2004.04.074. [Cross Ref]
  • Fischer B. Accuracy of binding mode prediction with a cascadic stochastic tunneling method. Proteins-Structure Function and Bioinformatics. 2007;68(1):195–204. doi: 10.1002/prot.21382. [PubMed] [Cross Ref]
  • Kokh DB, Wenzel WG. Flexible side chain models improve enrichment rates in in silico screening. Journal of Medicinal Chemistry. 2008;51(19):5919–5931. doi: 10.1021/jm800217k. [PubMed] [Cross Ref]
  • Fischer B, Fukuzawa K, Wenzel W. Receptor-specific scoring functions derived from quantum chemical models improve affinity estimates for in-silico drug discovery. Proteins-Structure Function and Bioinformatics. 2008;70(4):1264–1273. doi: 10.1002/prot.21607. [PubMed] [Cross Ref]

Articles from Journal of Cheminformatics are provided here courtesy of Springer