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Molecules 2016, 21(11), 1604; doi:10.3390/molecules21111604

AutoDock-GIST: Incorporating Thermodynamics of Active-Site Water into Scoring Function for Accurate Protein-Ligand Docking

Department of Computational Science, Graduate School of System Informatics, Kobe University, 1-1 Rokkodai, Nada, Kobe, Hyogo 657-8501, Japan
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Academic Editor: James W. Gauld
Received: 12 October 2016 / Revised: 15 November 2016 / Accepted: 16 November 2016 / Published: 23 November 2016
(This article belongs to the Collection Molecular Docking)
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Abstract

Water plays a significant role in the binding process between protein and ligand. However, the thermodynamics of water molecules are often underestimated, or even ignored, in protein-ligand docking. Usually, the free energies of active-site water molecules are substantially different from those of waters in the bulk region. The binding of a ligand to a protein causes a displacement of these waters from an active site to bulk, and this displacement process substantially contributes to the free energy change of protein-ligand binding. The free energy of active-site water molecules can be calculated by grid inhomogeneous solvation theory (GIST), using molecular dynamics (MD) and the trajectory of a target protein and water molecules. Here, we show a case study of the combination of GIST and a docking program and discuss the effectiveness of the displacing gain of unfavorable water in protein-ligand docking. We combined the GIST-based desolvation function with the scoring function of AutoDock4, which is called AutoDock-GIST. The proposed scoring function was assessed employing 51 ligands of coagulation factor Xa (FXa), and results showed that both scoring accuracy and docking success rate were improved. We also evaluated virtual screening performance of AutoDock-GIST using FXa ligands in the directory of useful decoys-enhanced (DUD-E), thus finding that the displacing gain of unfavorable water is effective for a successful docking campaign. View Full-Text
Keywords: protein-ligand docking; virtual screening; grid inhomogeneous solvation theory (GIST); AutoDock4; binding-site water protein-ligand docking; virtual screening; grid inhomogeneous solvation theory (GIST); AutoDock4; binding-site water
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Uehara, S.; Tanaka, S. AutoDock-GIST: Incorporating Thermodynamics of Active-Site Water into Scoring Function for Accurate Protein-Ligand Docking. Molecules 2016, 21, 1604.

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