title: Virtual screening and structure-based discovery of indole acylguanidines as potent β-secretase (BACE1) inhibitors.
abstract: Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE1) is a key step in generating the N-terminal of β-amyloid (Aβ), which further forms into amyloid plaques that are considered as the hallmark of Alzheimer's disease. Inhibitors of BACE1 can reduce the levels of Aβ and thus have a therapeutic potential for treating the disease. We report here the identification of a series of small molecules bearing an indole acylguanidine core structure as potent BACE1 inhibitors. The initial weak fragment was discovered by virtual screening, and followed with a hit-to-lead optimization. With the aid of co-crystal structures of two discovered inhibitors (compounds 19 and 25) with BACE1, we explored the SAR around the indole and aryl groups, and obtained several BACE1 inhibitors about 1,000-fold more potent than the initial fragment hit. Accompanying the lead optimization, a previously under-explored sub-site opposite the flap loop was redefined as a potential binding site for later BACE1 inhibitor design.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Yiquan
authors.initials: Y
authors.lastname: Zou
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Wuyan
authors.initials: W
authors.lastname: Chen
authors.forename: Tiantian
authors.initials: T
authors.lastname: Chen
authors.forename: Lanping
authors.initials: L
authors.lastname: Ma
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Bing
authors.initials: B
authors.lastname: Xiong
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D055808:Drug Discovery; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D006146:Guanidines; D007211:Indoles; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human