Journal
JOURNAL OF COMPUTATIONAL CHEMISTRY
Volume 32, Issue 13, Pages 2800-2809Publisher
WILEY
DOI: 10.1002/jcc.21859
Keywords
checkpoint kinase 1 inhibitors; induced-fit docking; QM/MM docking; binding-free energy; Prime/MM-GBSA
Categories
Funding
- Program for New Century Excellent Talents in University [NCET-07-0399]
- National Natural Science Foundation of China [20905033]
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Developing chemicals that inhibit checkpoint kinase 1 (Chk1) is a promising adjuvant therapeutic to improve the efficacy and selectivity of DNA-targeting agents. Reliable prediction of binding-free energy and binding affinity of Chk1 inhibitors can provide a guide for rational drug design. In this study, multiple docking strategies and Prime/Molecular Mechanics Generalized Born Surface Area (Prime/MM-GBSA) calculation were applied to predict the binding mode and free energy for a series of benzoisoquinolinones as Chk1 inhibitors. Reliable docking results were obtained using induced-fit docking and quantum mechanics/molecular mechanics (QM/MM) docking, which showed superior performance on both ligand binding pose and docking score accuracy to the rigid-receptor docking. Then, the Prime/MM-GBSA method based on the docking complex was used to predict the binding-free energy. The combined use of QM/MM docking and Prime/MM-GBSA method could give a high correlation between the predicted binding-free energy and experimentally determined pIC(50). The molecular docking combined with Prime/MM-GBSA simulation can not only be used to rapidly and accurately predict the binding-free energy of novel Chk1 inhibitors but also provide a novel strategy for lead discovery and optimization targeting Chk1. (C) 2011 Wiley Periodicals, Inc. J Comput Chem 32: 2800-2808, 2011
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