Effects of protein conformation in docking: Improved pose prediction through protein pocket adaptation

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158-9001, USA.
Journal of Computer-Aided Molecular Design (Impact Factor: 2.99). 05/2009; 23(6):355-74. DOI: 10.1007/s10822-009-9266-3
Source: PubMed


Computational methods for docking ligands have been shown to be remarkably dependent on precise protein conformation, where acceptable results in pose prediction have been generally possible only in the artificial case of re-docking a ligand into a protein binding site whose conformation was determined in the presence of the same ligand (the "cognate" docking problem). In such cases, on well curated protein/ligand complexes, accurate dockings can be returned as top-scoring over 75% of the time using tools such as Surflex-Dock. A critical application of docking in modeling for lead optimization requires accurate pose prediction for novel ligands, ranging from simple synthetic analogs to very different molecular scaffolds. Typical results for widely used programs in the "cross-docking case" (making use of a single fixed protein conformation) have rates closer to 20% success. By making use of protein conformations from multiple complexes, Surflex-Dock yields an average success rate of 61% across eight pharmaceutically relevant targets. Following docking, protein pocket adaptation and rescoring identifies single pose families that are correct an average of 67% of the time. Consideration of the best of two pose families (from alternate scoring regimes) yields a 75% mean success rate.

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    • "This bulky group maybe liable to destroy the proper binding orientation position between the compounds and the NNRTI binding site, which have been called as the horseshoe conformational shape (Gu et al., 2011). Superposition of all the compounds using the conformations after docking (Jain, 2009) in the NNRTI pocket showed that an unfavorable connection appeared in some compounds with lower activities, in which the cyclopropyl group was protruding into the binding pocket instead of the phenyl ring A (Fig. 3) (Spitzer and Jain, 2012). Because the previous relative SAR studies have showed that p–p main interactions were present between the phenyl ring A of the ligands and residues Tyr181 and Tyr188 in the allosteric binding pocket (Tian et al., 2010), a cyclopropyl might therefore weaken the p–p interaction (Thakur et al., 2008). "
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