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J Med Chem. 2012 Jan 26;55(2):623-38. doi: 10.1021/jm2005145. Epub 2012 Jan 13.

A force field with discrete displaceable waters and desolvation entropy for hydrated ligand docking.

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1
Molecular Graphics Lab, Department of Molecular Biology, MB-112, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037-1000, United States.

Abstract

In modeling ligand-protein interactions, the representation and role of water are of great importance. We introduce a force field and hydration docking method that enables the automated prediction of waters mediating the binding of ligands with target proteins. The method presumes no prior knowledge of the apo or holo protein hydration state and is potentially useful in the process of structure-based drug discovery. The hydration force field accounts for the entropic and enthalpic contributions of discrete waters to ligand binding, improving energy estimation accuracy and docking performance. The force field has been calibrated and validated on a total of 417 complexes (197 training set; 220 test set), then tested in cross-docking experiments, for a total of 1649 ligand-protein complexes evaluated. The method is computationally efficient and was used to model up to 35 waters during docking. The method was implemented and tested using unaltered AutoDock4 with new force field tables.

PMID:
22148468
PMCID:
PMC3319101
DOI:
10.1021/jm2005145
[Indexed for MEDLINE]
Free PMC Article
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