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Computationally Elucidating the Binding Kinetics for Different AChE Inhibitors to Access the Rationale for Improving the Drug Efficacy

文献类型：期刊论文

作者Bai, Fang1,2; Jiang, Hualiang3,4
刊名JOURNAL OF PHYSICAL CHEMISTRY B
出版日期2022-09-28
页码9
ISSN号1520-6106
DOI10.1021/acs.jpcb.2c03632
通讯作者Bai, Fang(baifang@shanghaitech.edu.cn)
英文摘要Traditional drug discovery is based on a binding affinity (thermodynamics)-driven paradigm. Numerous examples, however, demonstrated that drug efficacy does not always depend only on binding affinity but positively correlates with binding kinetics, that is, the dissociation rate constant (koff). Binding free energy landscape (BFEL) constructor is a computational binding kinetics prediction method, previously developed by us, that estimates the binding kinetics for ligand-protein based on their constructed binding free energy landscape, but it also reveals the detailed molecular mechanism of the binding event, hence, providing the position of transition states at the molecular level to modify/improve the binding kinetics. Acetylcholinesterase (AChE) is a well-known Alzheimer's disease (AD) target for which there is still not an ideal drug on the market. Therefore, to improve the drug design strategy for AD, the binding kinetics and binding molecular mechanisms of the four inhibitors of AChE, that is, E2020 (Aricept), HupA, Rivastigmine, and Galantamine, were studied. Also, the differentiation of the binding kinetics between mAChE and TcAChE was studied to evaluate the sensitiveness of BFEL constructor. The flexibility of molecules has a noticeable effect on the nature of BFEL. To the same target, flexible molecules (i.e., E2020 and Rivastigmine) which contain more rotatable bonds tend to have more complicated BFELs reflecting more complicated molecular action mechanisms than the rigid ones (i.e., HupA and Galantamine), which therefore could be more challenging to be optimized. The binding kinetics is highly dependent on the structure of the molecules, such as the length and the functional groups. Therefore, E2020 presents better binding kinetic and thermodynamic properties with either TcAChE or mAChE. Therefore, it is the most promising lead drug for binding kinetics-based drug design. In addition, the binding kinetics of a drug may present different values in the proteins of different organisms because the residue compositions of the binding gorges of the targets are variant, that is, E2020 shows lower binding affinity and association energy barrier in binding with mAChE than TcAChE. However, HupA presents a better binding property with TcAChE than mAChE.
WOS关键词ALZHEIMERS-DISEASE ; ENERGY LANDSCAPE ; ACETYLCHOLINESTERASE ; GENERATION ; DISCOVERY ; MECHANISM
资助项目Lingang Laboratory[LG202102-01-03] ; National Natural Science Foundation of China[82003654] ; Shanghai Science and Technology Development Funds[20QA1406400] ; Shanghai Science and Technology Development Funds[22ZR1441400] ; ShanghaiTech University
WOS研究方向Chemistry
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000863627500001
源URL[http://119.78.100.183/handle/2S10ELR8/302733]  
专题中国科学院上海药物研究所
通讯作者Bai, Fang
作者单位1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
2.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Sch Informat Sci & Technol, Shanghai 201210, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
4.Shanghai Tech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China
推荐引用方式
GB/T 7714		 Bai, Fang,Jiang, Hualiang. Computationally Elucidating the Binding Kinetics for Different AChE Inhibitors to Access the Rationale for Improving the Drug Efficacy[J]. JOURNAL OF PHYSICAL CHEMISTRY B,2022:9.
APA Bai, Fang,&Jiang, Hualiang.(2022).Computationally Elucidating the Binding Kinetics for Different AChE Inhibitors to Access the Rationale for Improving the Drug Efficacy.JOURNAL OF PHYSICAL CHEMISTRY B,9.
MLA Bai, Fang,et al."Computationally Elucidating the Binding Kinetics for Different AChE Inhibitors to Access the Rationale for Improving the Drug Efficacy".JOURNAL OF PHYSICAL CHEMISTRY B (2022):9.

入库方式： OAI收割

来源：上海药物研究所

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