title: Design and prediction of new acetylcholinesterase inhibitor via quantitative structure activity relationship of huprines derivatives.
abstract: Acetylcholinesterase (AChE) is an important enzyme in the pathogenesis of Alzheimer's disease (AD). Comparative quantitative structure-activity relationship (QSAR) analyses on some huprines inhibitors against AChE were carried out using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram QSAR (HQSAR) methods. Three highly predictive QSAR models were constructed successfully based on the training set. The CoMFA, CoMSIA, and HQSAR models have values of r (2) = 0.988, q (2) = 0.757, ONC = 6; r (2) = 0.966, q (2) = 0.645, ONC = 5; and r (2) = 0.957, q (2) = 0.736, ONC = 6. The predictabilities were validated using an external test sets, and the predictive r (2) values obtained by the three models were 0.984, 0.973, and 0.783, respectively. The analysis was performed by combining the CoMFA and CoMSIA field distributions with the active sites of the AChE to further understand the vital interactions between huprines and the protease. On the basis of the QSAR study, 14 new potent molecules have been designed and six of them are predicted to be more active than the best active compound 24 described in the literature. The final QSAR models could be helpful in design and development of novel active AChE inhibitors.
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.
authors.forename: Shuqun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. zuozhili@mail.kib.ac.cn.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zuozhili@mail.kib.ac.cn.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D000634:Aminoquinolines / Q000737:chemistry* / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology; D013619:Tacrine / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000470:Alkaloids; D000634:Aminoquinolines; D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D012717:Sesquiterpenes; C050426:huperzine A; D013619:Tacrine
keywords: AChE; AD; CoMFA; CoMSIA; HQSAR; Huprines inhibitors