Molecular Mechanism of Binding Selectivity of Inhibitors toward BACE1 and BACE2 Revealed by Multiple Short Molecular Dynamics Simulations and Free-Energy Predictions
文献类型：期刊论文
| 作者 | Chen, Jianzhong2; Wang, Jinan3; Yin, Baohua1; Pang, Laixue2; Wang, Wei2; Zhu, Weiliang3
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| 刊名 | ACS CHEMICAL NEUROSCIENCE
 |
| 出版日期 | 2019-10-01 |
| 卷号 | 10期号:10页码:4303-4318 |
| 关键词 | beta-amyloid cleaving enzyme binding selectivity MSMD hierarchical clustering analysis MM-GBSA |
| ISSN号 | 1948-7193 |
| DOI | 10.1021/acschemneuro.9b00348 |
| 通讯作者 | Chen, Jianzhong(chenjianzhong1970@163.com) ; Zhu, Weiliang(wlzhu@simm.ac.cn) |
| 英文摘要 | The beta-amyloid cleaving enzymes 1 and 2 (BACE1 and BACE2) have been regarded as the prospective targets for clinically treating Alzheimer's disease (AD) in the last two decades. Thus, insight into the binding differences of inhibitors to BACE1 and BACE2 is of significance for designing highly selective inhibitors toward the two proteins. In this work, multiple short molecular dynamics (MSMD) simulations are coupled with the molecular mechanics generalized Born surface area (MM-GBSA) method to probe the binding selectivity of three inhibitors DBO, CS9, and SC7 on BACE1 over BACE2. The results show that the entropy effect plays a key role in selectivity identification of inhibitors toward BACE1 and BACE2, which determines that DBO has better selectivity toward BACE2 over BACE1, while CS9 and CS7 can more favorably bind to BACE1 than BACE2. The hierarchical clustering analysis based on energetic contributions of residues suggests that BACE1 and BACE2 share the common hot interaction spots. The residue-based free-energy decomposition method was applied to compute the inhibitor-residue interaction spectrum, and the results recognize four common binding subpockets corresponding to the different groups of inhibitors, which can be used as efficient targets for designing highly selective inhibitors toward BACE1 and BACE2. Therefore, these results provide a useful molecular basis and dynamics information for development of highly selective inhibitors targeting BACE1 and BACE2. |
| WOS关键词 | PARTICLE MESH EWALD ; ALZHEIMERS-DISEASE ; HIV-1 PROTEASE ; EFFICIENT GENERATION ; LIGAND SELECTIVITY ; CRYSTAL-STRUCTURE ; COMPLEX-FORMATION ; AM1-BCC MODEL ; AMYLOID-BETA ; APP GENE |
| 资助项目 | National Key Research and Development Program[2016YFA0502301] ; National Natural Science Foundation of China[21403283] ; National Natural Science Foundation of China[81573350] ; Shandong Provincial Natural Science Foundation[ZR2017MA040] ; key research and development project of Shandong province[2018GSF121014] ; key research and development project of Shandong province[2019GGX102050] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology |
| 语种 | 英语 |
| WOS记录号 | WOS:000491219000014 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/282733]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Chen, Jianzhong; Zhu, Weiliang |
| 作者单位 | 1.Shandong Univ Tradit Chinese Med, Sch Pharm, Jinan 250355, Shandong, Peoples R China 2.Shandong Jiaotong Univ, Sch Sci, Jinan 250357, Shandong, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Jianzhong,Wang, Jinan,Yin, Baohua,et al. Molecular Mechanism of Binding Selectivity of Inhibitors toward BACE1 and BACE2 Revealed by Multiple Short Molecular Dynamics Simulations and Free-Energy Predictions[J]. ACS CHEMICAL NEUROSCIENCE,2019,10(10):4303-4318. |
| APA | Chen, Jianzhong,Wang, Jinan,Yin, Baohua,Pang, Laixue,Wang, Wei,&Zhu, Weiliang.(2019).Molecular Mechanism of Binding Selectivity of Inhibitors toward BACE1 and BACE2 Revealed by Multiple Short Molecular Dynamics Simulations and Free-Energy Predictions.ACS CHEMICAL NEUROSCIENCE,10(10),4303-4318. |
| MLA | Chen, Jianzhong,et al."Molecular Mechanism of Binding Selectivity of Inhibitors toward BACE1 and BACE2 Revealed by Multiple Short Molecular Dynamics Simulations and Free-Energy Predictions".ACS CHEMICAL NEUROSCIENCE 10.10(2019):4303-4318. |
入库方式： OAI收割
来源：上海药物研究所
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