【摘 要】
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An accepted view is that transition state (TS) is central to understanding enzymatic catalysis.In general,the TS structure often binds more tightly to the e
【机 构】
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SchoolofPharmaceuticalScience,SunYat-SenUniversity,Guangzhou,510006,China
【出 处】
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第七届国际理论化学、分子模拟和生命科学研讨会暨科学计算和模拟软件发展平台学术交流会
论文部分内容阅读
An accepted view is that transition state (TS) is central to understanding enzymatic catalysis.In general,the TS structure often binds more tightly to the enzyme than either the substrate or the product.Therefore,it could guide the design of TS analog as enzyme inhibitor to increase the selectivity.The state-of-the-art DFT-based QM/MM MD simulations,which not only allows for a first-principle description of the dynamics such as bond breaking and forming in catalytic site but also properly including effects of the heterogeneous and fluctuating protein environment,was thought to be a powerful tool to observe TS structure directly.We studied the deacetylation catalytic mechanism in HDAC8 and obseved the flexibility of zinc coordination.Furthermore,our simulation results confirmed the bi-/mono-/weak- dentate characteristics between hydroxamic acid and zinc in HDAC8/7/4,and suggested a novel mechanism that the different chelation mode in HDACs is modulated by water access to the linker binding channel.Herein,we would like to talk about our very recent work on reaction-mechanism-based HDAC2 inhibitor design,the inhibitory activity of the designed novel TS-like inhibitor was confirmed by IC50 assay.
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