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MS-DOCK: Accurate multiple conformation generator and rigid docking protocol for multi-step virtual ligand screening

DOI: 10.1186/1471-2105-9-184

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Abstract:

Here we present an efficient multiple conformation rigid-body docking approach, MS-DOCK, which is based on the program DOCK. This approach can be used as the first step of a multi-stage docking/scoring protocol. First, we developed and validated the Multiconf-DOCK tool that generates several conformers per input ligand. Then, each generated conformer (bioactives and 37970 decoys) was docked rigidly using DOCK6 with our optimized protocol into seven different receptor-binding sites. MS-DOCK was able to significantly reduce the size of the initial input library for all seven targets, thereby facilitating subsequent more CPU demanding flexible docking procedures.MS-DOCK can be easily used for the generation of multi-conformer libraries and for shape-based filtering within a multi-step structure-based screening protocol in order to shorten computation times.Recent advances in the human genomics and proteomics projects have significantly contributed to the large number of macromolecular targets entering drug discovery programs. Along the same line, over 10 million organic compounds are presently available from chemical vendors and can be used in high throughput screening (HTS) experiments or in silico computations. However the escalating costs of both, experimental assays and hardware/software, highlight the need for development of novel approaches to assist rapid and efficient hit identification. Here we focus our attention on structure-based virtual ligand screening (SBVLS) methods [1-4] since they are known to be effective for library prioritization in the context of a drug discovery campaign or chemogenomics initiatives [5-7]. Numerous free or open-source VLS tools are available to academic groups [8,9] and such in silico methods play a major role in facilitating the identification of new lead compounds.The ideal SBVLS method should predict both, the pose and the affinity of the ligands and be able to deal with flexibility [10]. Such tool does not exist today and try

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