OptiDock: virtual HTS of combinatorial libraries by efficient sampling of binding modes in product space

Journal of Combinatorial Chemistry
Dennis G SprousRobert D Clark

Abstract

Products from combinatorial libraries generally share a common core structure that can be exploited to improve the efficiency of virtual high-throughput screening (vHTS). In general, it is more efficient to find a method that scales with the total number of reagents (Sigma growth) rather with the number of products (Pi growth). The OptiDock methodology described herein entails selecting a diverse but representative subset of compounds that span the structural space encompassed by the full library. These compounds are docked individually using the FlexX program (Rarey, M.; Kramer, B.; Lengauer, T.; Klebe, G. J. Mol. Biol. 1995, 251, 470-489) to define distinct docking modes in terms of reference placements for combinatorial core atoms. Thereafter, substituents in R-cores (consisting of the core structure substituted at a single variation site) are docked, keeping the core atoms fixed at the coordinates dictated by each reference placement. Interaction energies are calculated for each docked R-core with respect to the target protein, and energies for whole compounds are calculated by finding the reference core placement for which the sum of corresponding R-core energies is most negative. The use of diverse whole compounds to defi...Continue Reading

References

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Citations

Nov 18, 2005·Journal of Computer-aided Molecular Design·Sukjoon YoonAnton Filikov
Oct 21, 2006·Journal of Computer-aided Molecular Design·Farhad SoltanshahiRobert D Clark
Jul 14, 2009·Journal of Computer-aided Molecular Design·Joe Zhongxiang ZhouTom Thacher
Feb 10, 2012·Current Pharmaceutical Design·Lu ChenShuxing Zhang
Jul 26, 2006·Expert Opinion on Drug Metabolism & Toxicology·Thomas HerzBernd Kramer
Mar 11, 2008·Current Opinion in Chemical Biology·Joe Zhongxiang Zhou
Mar 27, 2007·Journal of Chemical Information and Modeling·Krystian EitnerJan Barciszewski

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