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DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations

a , 1 , 2 , 3

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protein, docking ligand, congruence

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      Abstract

      The ability to accurately and effectively predict the interaction between proteins and small drug-like compounds has long intrigued researchers for pedagogic, humanitarian and economic reasons. Protein docking methods (AutoDock, GOLD, DOCK, FlexX and Glide to name a few) rank a large number of possible conformations of protein-ligand complexes using fast algorithms. Previously, it has been shown that structural congruence leading to the same enzymatic function necessitates the congruence of electrostatic properties (CLASP). The current work presents a methodology for docking a ligand into a target protein, provided that there is at least one known holoenzyme with ligand bound - DOCLASP (Docking using CLASP). The contact points of the ligand in the holoenzyme defines a motif, which is used to query the target enzyme using CLASP. If there are significant matches, the holoenzyme and the target protein are superimposed based on congruent atoms. The same linear and rotational transformations are also applied to the ligand, thus creating a unified coordinate framework having the holoenzyme, the ligand and the target enzyme. In the current work, the dipeptidyl peptidase-IV inhibitor vildagliptin was docked to the PI-PLC structure complexed with myo-inositol using DOCLASP. Also, corroboration of the docking of phenylthiourea to the modelled structure of polyphenol oxidase (JrPPO1) from walnut is provided based on the subsequently solved structure of JrPPO1 (PDBid:5CE9). Analysis of the binding of the antitrypanosomial drug suramin to nine non-homologous proteins in the PDB database shows a diverse set of binding motifs, and multiple binding sites in the phospholipase A2-likeproteins from the Bothrops genus of pitvipers. The conformational changes in the suramin molecule on binding highlights the challenges in docking flexible ligands into an already ’plastic’ binding site. Thus, DOCLASP presents a method for ’soft docking’ ligands to proteins with low computational requirements.

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      Most cited references 61

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        We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique. (c) 2009 Wiley Periodicals, Inc.
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          Evaluation of the electrostatic properties of biomolecules has become a standard practice in molecular biophysics. Foremost among the models used to elucidate the electrostatic potential is the Poisson-Boltzmann equation; however, existing methods for solving this equation have limited the scope of accurate electrostatic calculations to relatively small biomolecular systems. Here we present the application of numerical methods to enable the trivially parallel solution of the Poisson-Boltzmann equation for supramolecular structures that are orders of magnitude larger in size. As a demonstration of this methodology, electrostatic potentials have been calculated for large microtubule and ribosome structures. The results point to the likely role of electrostatics in a variety of activities of these structures.
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            Author and article information

            Affiliations
            [1 ]Plant Sciences Department, University of California, Davis, CA, 95616, USA
            [2 ]Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, 400 005, India
            [3 ]Celia Engineers, Navi Mumbai, India
            [1 ]Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, Kolkata, India
            Tata Institute of Fundamental Research, India
            [1 ]Department of Computer Science, George Mason University, Fairfax, VA, USA
            Tata Institute of Fundamental Research, India
            [1 ]Department of Computer Science, George Mason University, Fairfax, VA, USA
            Tata Institute of Fundamental Research, India
            George Mason University, USA
            [1 ]Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, Kolkata, India
            Tata Institute of Fundamental Research, India
            Author notes

            Competing interests: No competing interests were disclosed.

            Journal
            F1000Res
            F1000Res
            F1000Research
            F1000Research
            F1000Research (London, UK )
            2046-1402
            16 June 2016
            2014
            : 3
            27429737 4934513 10.12688/f1000research.5145.3
            Copyright: © 2016 Chakraborty S

            This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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            Funding
            The author(s) declared that no grants were involved in supporting this work.
            Categories
            Research Note
            Articles
            Bioinformatics
            Protein Chemistry & Proteomics

            protein, docking ligand, congruence

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