Maximum Common Binding Modes (MCBM): Consensus Docking Scoring Using Multiple Ligand Information and Interaction Fingerprints

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• 作者：Steffen Renner ; Swetlana Derksen ; Sebastian Radestock ; Fabian M&ouml ; rchen
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2008
• 出版时间：February 2008
• 年：2008
• 卷：48
• 期：2
• 页码：319 - 332
• 全文大小：1062K
• 年卷期：v.48,no.2(February 2008)
• ISSN：1549-960X

文摘

Improving the scoring functions for small molecule-protein docking is a highly challenging task in currentcomputational drug design. Here we present a novel consensus scoring concept for the prediction of bindingmodes for multiple known active ligands. Similar ligands are generally believed to bind to their receptor ina similar fashion. The presumption of our approach was that the true binding modes of similar ligandsshould be more similar to each other compared to false positive binding modes. The number of conserved(consensus) interactions between similar ligands was used as a docking score. Patterns of interactions weremodeled using ligand receptor interaction fingerprints. Our approach was evaluated for four different datasets of known cocrystal structures (CDK-2, dihydrofolate reductase, HIV-1 protease, and thrombin). Dockingposes were generated with FlexX and rescored by our approach. For comparison the CScore scoring functionsfrom Sybyl were used, and consensus scores were calculated thereof. Our approach performed better thanindividual scoring functions and was comparable to consensus scoring. Analysis of the distribution of dockingposes by self-organizing maps (SOM) and interaction fingerprints confirmed that clusters of docking posescomposed of multiple ligands were preferentially observed near the native binding mode. Being conceptuallyunrelated to commonly used docking scoring functions our approach provides a powerful method tocomplement and improve computational docking experiments.