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Binding Mechanism and Molecular Design of benzimidazole/benzothiazole derivatives as potent Abl T315I mutant Inhibitors
Wu Wen-Juan
Author NameAffiliationE-mail
Wu Wen-Juan Guangdong Pharmaceutical University wuwenjuan83@126.com 
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 paper, a multistep computational framework combining the three dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, 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 was 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 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 have been designed and presented to experimenters for reference.
Key words:  Abl T315I mutant inhibitor, Benzimidazole/benzothiazole derivative, 3D-QSAR, Docking study, MD simulation, Molecular Design
FundProject:
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
吴文娟
摘要:
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 paper, a multistep computational framework combining the three dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, 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 was 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 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 have been designed and presented to experimenters for reference.
关键词:  T315I突变型Abl抑制剂, 苯并咪唑/苯并噻唑类衍生物,三维定量构效关系,分子对接,分子动力学模拟,分子设计
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