Molecular modeling study of checkpoint kinase 1 inhibitors by multiple docking strategies and prime/MM-GBSA calculation |
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Authors: | Du Juan Sun Huijun Xi Lili Li Jiazhong Yang Ying Liu Huanxiang Yao Xiaojun |
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Affiliation: | Department of Chemistry, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China. |
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Abstract: | 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. |
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Keywords: | checkpoint kinase 1 inhibitors induced‐fit docking QM/MM docking binding‐free energy Prime/MM–GBSA |
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