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Abstract
BackgroundThe number of protein targets with a known or predicted tri-dimensional structure and of drug-like chemical compounds is growing rapidly and so is the need for new therapeutic compounds or chemical probes. Performing flexible structure-based virtual screening computations on thousands of targets with millions of molecules is intractable to most laboratories nor indeed desirable. Since shape complementarity is of primary importance for most protein-ligand interactions, we have developed a tool/protocol based on rigid-body docking to select compounds that fit well into binding sites.ResultsHere 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.ConclusionMS-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.
Highlights
The number of protein targets with a known or predicted tri-dimensional structure and of drug-like chemical compounds is growing rapidly and so is the need for new therapeutic compounds or chemical probes
MS-DOCK approach In this work we describe an efficient approach MS-DOCK based on DOCK to rapidly screen a molecular database and to enrich the output collection in molecules having good shape complementarity with a given protein target binding site
The MS-DOCK approach involves two main steps: first, generating multiple 3D conformers for the flexible molecules present in the input chemical library, this step is performed with the in-house developed tool Multiconf-DOCK based on the systematic search approach available in DOCK5 [33]; second, all multiple conformations are rigidly docked with DOCK6
Summary
The number of protein targets with a known or predicted tri-dimensional structure and of drug-like chemical compounds is growing rapidly and so is the need for new therapeutic compounds or chemical probes. 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 trying to dock millions of molecules on thousands of targets with the available flexible docking methods eventually followed by real computations of binding affinities is out of reach to most research groups. A number of tools and protocols (i.e., multi-step SBVLS protocols) exploit this notion of rigid-body docking or at least use approaches that analyze the shape or the shape complementarity only, as a first step of a hierarchical procedure, to rapidly reduce the size of the compound collections prior to using more accurate and time consuming docking/scoring computations [16,17,18,19,20,21]
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