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Binding Mechanism and Molecular Design of Benzimidazole/Benzothiazole Derivatives as Potent Abl T315I Mutant Inhibitors
Wei-cong Lin,She-pei Tan,Sheng-fu Zhou,Xiao-jie Zheng,Wen-juan Wu*,Kang-cheng Zheng
Author NameAffiliationE-mail
Wei-cong Lin   
She-pei Tan   
Sheng-fu Zhou   
Xiao-jie Zheng   
Wen-juan Wu*  wwj@gdpu.edu.cn 
Kang-cheng Zheng   
Abstract:
Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T315I mutant, makes the search for new Abl T315I inhibitors a very interesting challenge in medicinal chemistry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, molecular dynamics (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 T315I. 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 T315I activities were designed and presented to experimenters for reference.
Key words:  Abl T315I mutant inhibitor  Benzimidazole/benzothiazole derivative  Three dimensional quantitative structure-activity relationship  Docking study  Molecular dynamics simulation  Molecular design
FundProject:This work was supported by the Science and Technology Program of Guangzhou (No.2013J4100071).We also heartily thank the College of Life Sciences,Sun Yat-sen University for the SYBYL 6.9 computation environment support.
苯并咪唑/苯并噻唑类T315I突变型Abl抑制剂的结合机理和分子设计
林伟聪,谭社培,周盛福,郑晓杰,吴文娟*,郑康成
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DOI:10.1063/1674-0068/30/cjcp1704066
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