title: Destabilization of Alzheimer's Aβ42 Protofibrils with a Novel Drug Candidate wgx-50 by Molecular Dynamics Simulations.
abstract: Alzheimer's disease (AD) is one of the most common dementia. The aggregation and deposition of the amyloid-β peptide (Aβ) in neural tissue is its characteristic symptom. To destabilize and dissolve Aβ fibrils, a number of candidate molecules have been proposed. wgx-50 is a compound extracted from Sichuan pepper (Zanthoxylum bungeanum) and a potential candidate drug for treating AD. Our early experiments show it is effective in disassembling Aβ42 aggregations. A series of molecular dynamics simulations were performed in this work to explain the molecular mechanism of the destabilization of Aβ42 protofibril by wgx-50. It is found that there were three possible stable binding sites including two sites in hydrophobic grooves on surface of Aβ protofibril that made no significant changes in Aβ structures and one site in the interior that caused destabilization of the protofibril. In this site, wgx-50 was packed against the side chains of I32 and L34, disrupted the D23-K28 salt bridges, and partially opened the tightly compacted two β-sheets. The results were confirmed by simulations at 320 K, where deeper insertion of wgx-50 into the whole protofibril was observed. The molecular mechanism of this novel drug candidate wgx-50 to disaggregate Aβ protofibril may provide some insight into the strategy of structure-based drug design for AD.
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Huai-Meng
authors.initials: HM
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Ruo-Xu
authors.initials: RX
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Yan-Jing
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Yun-Long
authors.initials: YL
authors.lastname: Pi
authors.affiliation: Medicine Engineering Research Center, School of Pharmacy, Chongqing Medical University , Chongqing 400016, China.
authors.forename: Yong-Hong
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Dong-Qing
authors.initials: DQ
authors.lastname: Wei
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D055808:Drug Discovery; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000178:Acrylamides; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C583359:lemairamin