Structure-Based Survey of the Binding Modes of BACE1 Inhibitors

doi:10.1021/acschemneuro.8b00420

	Structure-Based Survey of the Binding Modes of BACE1 Inhibitors
	Hu, Hangchen; Chen, Zhaoqiang; Xu, Xiang; Xuo, Yechun
刊名	ACS CHEMICAL NEUROSCIENCE
	2019-02-01
卷号	10 期号:2 页码:880-889
关键词	BACE1 Alzheimer's disease inhibitor ligand binding mode subsite substructure
ISSN号	1948-7193
DOI	10.1021/acschemneuro.8b00420
通讯作者	Xuo, Yechun(ycxu@simm.ac.cn)
英文摘要	BACE1 is a key aspartic protease that cleaves the amyloid precursor protein to generate of the amyloid peptide that is believed to be responsible for the Alzheimer's disease amyloid cascade. It is thus recognized as a promising therapeutic target for Alzheimer's disease treatment, and large efforts have been made in the discovery of novel BACE1 inhibitors. This Review presents a systematic mining of BACE1 inhibitors based on 354 crystal structures of the BACE1 catalytic domain in complex with ligands in the Protein Data Bank. A thorough exploration on the frequency as well as the patterns of residue-ligand interactions enables us to subdivide the ligand binding pocket into 10 subsites and then identify favorable substructures of ligands for each subsite. In addition, it is found that the assembly of subsites with an 8-like shape is responsible to bind all inhibitors and four major ligand binding modes are revealed. Thus, such a systematic survey deepens our understanding of the structural requirements for establishment of BACE1-ligand interactions that determine the affinity of a ligand to BACE1, which is pivotal for structure-based lead optimization and design of novel inhibitors.
资助项目	National Key R&D Program of China[2016YFA0502301] ; National Key R&D Program of China[2017YFB0202604] ; National Natural Science Foundation of China[81661148046]
WOS关键词	STRUCTURE-BASED DESIGN ; AMYLOID PRECURSOR PROTEIN ; BETA-SECRETASE INHIBITORS ; X-RAY CRYSTALLOGRAPHY ; IN-VIVO REDUCTION ; ALZHEIMERS-DISEASE ; PEPTIDOMIMETIC INHIBITORS ; BIOLOGICAL EVALUATION ; SELECTIVE INHIBITORS ; CRYSTAL-STRUCTURE
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000459642700012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/290465]
专题	中国科学院上海药物研究所
通讯作者	Xuo, Yechun
作者单位	Chinese Acad Sci, CAS Key Lab Receptor Res, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Hu, Hangchen,Chen, Zhaoqiang,Xu, Xiang,et al. Structure-Based Survey of the Binding Modes of BACE1 Inhibitors[J]. ACS CHEMICAL NEUROSCIENCE,2019,10(2):880-889.
APA	Hu, Hangchen,Chen, Zhaoqiang,Xu, Xiang,&Xuo, Yechun.(2019).Structure-Based Survey of the Binding Modes of BACE1 Inhibitors.ACS CHEMICAL NEUROSCIENCE,10(2),880-889.
MLA	Hu, Hangchen,et al."Structure-Based Survey of the Binding Modes of BACE1 Inhibitors".ACS CHEMICAL NEUROSCIENCE 10.2(2019):880-889.