title: Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer's disease.
abstract: Acetylcholinesterase (AChE) is one of the key targets of drugs for treating Alzheimer's disease (AD). Tacrine is an approved drug with AChE-inhibitory activity. In this paper, 3D-QSAR, molecular docking, and molecular dynamics were carried out in order to study 60 tacrine derivatives and their AChE-inhibitory activities. 3D-QSAR modeling resulted in an optimal CoMFA model with q(2) = 0.552 and r(2) = 0.983 and an optimal CoMSIA model with q(2) = 0.581 and r(2) = 0.989. These QSAR models also showed that the steric and H-bond fields of these compounds are important influences on their activities. The interactions between these inhibitors and AChE were further explored through molecular docking and molecular dynamics simulation. A few key residues (Tyr70, Trp84, Tyr121, Trp279, and Phe330) at the binding site of AChE were identified. The results of this study improve our understanding of the mechanisms of AChE inhibitors and afford valuable information that should aid the design of novel potential AChE inhibitors. Graphical Abstract Superposition of backbone atoms of the lowest-energy structure obtained from MD simulation (magenta) onto those of the structure of the initial molecular docking model (green).
authors.affiliation: Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, Hefei, 230009, Anhui, China.|Anhui Province Key Laboratory of R&D of Chinese Medicine, Anhui University of Chinese Medicine, 103 Meishan Road, Hefei, 230038, Anhui, China.
authors.forename: An
authors.initials: A
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA.|Key Laboratory of Medicinal and Edible Plants Resources Development, School of Bioengineering, Chengdu University, Chengdu, 610106, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA.|Key Laboratory of Medicinal and Edible Plants Resources Development, School of Bioengineering, Chengdu University, Chengdu, 610106, China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Anhui Province Key Laboratory of R&D of Chinese Medicine, Anhui University of Chinese Medicine, 103 Meishan Road, Hefei, 230038, Anhui, China.
authors.forename: Guochen
authors.initials: G
authors.lastname: Zhong
authors.affiliation: Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, Hefei, 230009, Anhui, China. panjian78@sina.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Pan
authors.affiliation: Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, Hefei, 230009, Anhui, China.
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, Hefei, 230009, Anhui, China. haling@mail.ustc.edu.cn.
authors.forename: Ailing
authors.initials: A
authors.lastname: Hui
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D013619:Tacrine; D000110:Acetylcholinesterase
keywords: 3D-QSAR; AChE inhibitor; Alzheimer’s disease; Molecular dynamics; Tacrine