文献类型：期刊文章

作　　者：林伟聪[1] 谭社培[1] 周盛福[1] 郑晓杰[1] 吴文娟[1] 郑康成[2]

机构地区：[1]广东药科大学药学院物理化学教研室,广州510006 [2]中山大学化学与化学工程学院,广州510275

出　　处：《Chinese Journal of Chemical Physics》

年　　份：2017

卷　　号：30

期　　号：4

起止页码：429-442

语　　种：中文

收录情况：AJ、CAS、CSCD、CSCD2017_2018、INSPEC、JST、RSC、SCIE、SCOPUS、ZGKJHX、普通刊

摘　　要：Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibitors a very interesting challenge in medicinal chem- istry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship （3D-QSAR）, molecular docking, molecular dy- namics （MD） simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T3151. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T3151 activities were designed and presented to experimenters for reference.

关 键 词：Abl T315I mutant inhibitor  Benzimidazole/benzothiazole derivative  Three dimensional quantitative structure-activity relationship  Docking study  Molecular dynamics simulation  Molecular design  

分 类 号：O]