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A Comprehensive Docking and MM/GBSA Rescoring Study of Ligand Recognition upon Binding Antithrombin [electronic resource].

Published
Washington, D.C. : United States. Dept. of Energy, 2017.
Oak Ridge, Tenn. : Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy
Physical Description
pages 1,631-1,639 : digital, PDF file
Additional Creators
Lawrence Livermore National Laboratory, United States. Department of Energy, and United States. Department of Energy. Office of Scientific and Technical Information
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Summary
A high-throughput virtual screening pipeline has been extended from single energetically minimized structure Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) rescoring to ensemble-average MM/GBSA rescoring. The correlation coefficient (R2) of calculated and experimental binding free energies for a series of antithrombin ligands has been improved from 0.36 to 0.69 when switching from the single-structure MM/GBSA rescoring to ensemble-average one. The electrostatic interactions in both solute and solvent are identified to play an important role in determining the binding free energy after the decomposition of the calculated binding free energy. Furthermore, the increasing negative charge of the compounds provides a more favorable electrostatic energy change but creates a higher penalty for the solvation free energy. Such a penalty is compensated by the electrostatic energy change, which results in a better binding affinity. A highly hydrophobic ligand is determined by the docking program to be a non-specific binder. Finally, these results have demonstrated that it is very important to keep a few top poses for rescoring, if the binding is non-specific or the binding mode is not well determined by the docking calculation.
Report Numbers
E 1.99:llnl-jrnl--677160
llnl-jrnl--677160
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Note
Published through SciTech Connect.
04/06/2017.
"llnl-jrnl--677160"
Current Topics in Medicinal Chemistry 17 14 ISSN 1568-0266 AM
Xiaohua Zhang; Horacio Perez-Sanchez; Felice C. Lightstone.
Funding Information
AC52-07NA27344
View MARC record | catkey: 23498810