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Title: A Comprehensive Docking and MM/GBSA Rescoring Study of Ligand Recognition upon Binding Antithrombin

Journal Article · · Current Topics in Medicinal Chemistry
 [1];  [1];  [1]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Biosciences and Biotechnology Division
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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.

Research Organization:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC52-07NA27344
OSTI ID:
1343037
Report Number(s):
LLNL-JRNL-677160
Journal Information:
Current Topics in Medicinal Chemistry, Vol. 17, Issue 14; ISSN 1568-0266
Publisher:
Bentham Science PublishersCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 92 works
Citation information provided by
Web of Science

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Analysis of Plant-derived Phytochemicals as Anti-cancer Agents Targeting Cyclin Dependent Kinase-2, Human Topoisomerase IIa and Vascular Endothelial Growth Factor Receptor-2 posted_content March 2020
Empirical Scoring Functions for Structure-Based Virtual Screening: Applications, Critical Aspects, and Challenges journal September 2018
Elucidating Binding Sites and Affinities of ERα Agonists and Antagonists to Human Alpha-Fetoprotein by In Silico Modeling and Point Mutagenesis journal January 2020
On Restraints in End-Point Protein-Ligand Binding Free Energy Calculations journal February 2019
In silico Prediction, Characterization, Molecular Docking, and Dynamic Studies on Fungal SDRs as Novel Targets for Searching Potential Fungicides Against Fusarium Wilt in Tomato journal October 2018

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
docking
MM/GBSA
rescoring
VinaLC
BINDSURF
binding affinity
molecular dynamics
antithrombin