title: Comprehensive 3D-QSAR and binding mode of BACE-1 inhibitors using R-group search and molecular docking.
abstract: The β-enzyme (BACE), which takes an active part in the processing of amyloid precursor protein, thereby leads to the production of amyloid-β (Aβ) in the brain, is a major therapeutic target against Alzheimer's disease. The present study is aimed at studying 3D-QSAR of BACE-1 inhibitors and their binding mode. We build a 3D-QSAR model involving 99 training BACE-1 inhibitors based on Topomer CoMFA, and 26 molecules are employed to validate the external predictive power of the model obtained. The multiple correlation coefficients of fitting modeling, leave one out cross validation, and external validation are 0.966, 0.767 and 0.784, respectively. Topomer search is used as a tool for virtual screening in lead-like compounds of ZINC databases (2012); as a result, we successfully design 30 new molecules with higher activity than that of all training and test inhibitors. Besides, Surflex-dock is employed to explore binding mode of the inhibitors studied when acting with BACE-1 enzyme. The result shows that the inhibitors closely interact with the key sites related to ASP93, THR133, GLN134, ASP289, GLY291, THR292, THR293, ASN294, ARG296 and SER386 of BACE-1.
authors.affiliation: Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Huang
authors.forename: Yonglan
authors.initials: Y
authors.lastname: Liu
authors.forename: Bozhi
authors.initials: B
authors.lastname: Shi
authors.forename: Yueting
authors.initials: Y
authors.lastname: Li
authors.forename: Guixue
authors.initials: G
authors.lastname: Wang
authors.forename: Guizhao
authors.initials: G
authors.lastname: Liang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: BACE-1; Molecular docking; Quantitative structure–activity relationship; Topomer CoMFA; Topomer search