title: Molecular modeling study of checkpoint kinase 1 inhibitors by multiple docking strategies and prime/MM-GBSA calculation.
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.
authors: Department of Chemistry, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China.
authors: Juan
authors: J
authors: Du
authors: Huijun
authors: H
authors: Sun
authors: Lili
authors: L
authors: Xi
authors: Jiazhong
authors: J
authors: Li
authors: Ying
authors: Y
authors: Yang
authors: Huanxiang
authors: H
authors: Liu
authors: Xiaojun
authors: X
authors: Yao
mesh_terms: D000071877:Checkpoint Kinase 1; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1