title: Discovery of novel mGluR1 antagonists: a multistep virtual screening approach based on an SVM model and a pharmacophore hypothesis significantly increases the hit rate and enrichment factor.
abstract: Development of glutamate non-competitive antagonists of mGluR1 (Metabotropic glutamate receptor subtype 1) has increasingly attracted much attention in recent years due to their potential therapeutic application for various nervous disorders. Since there is no crystal structure reported for mGluR1, ligand-based virtual screening (VS) methods, typically pharmacophore-based VS (PB-VS), are often used for the discovery of mGluR1 antagonists. Nevertheless, PB-VS usually suffers a lower hit rate and enrichment factor. In this investigation, we established a multistep ligand-based VS approach that is based on a support vector machine (SVM) classification model and a pharmacophore model. Performance evaluation of these methods in virtual screening against a large independent test set, M-MDDR, show that the multistep VS approach significantly increases the hit rate and enrichment factor compared with the individual SB-VS and PB-VS methods. The multistep VS approach was then used to screen several large chemical libraries including PubChem, Specs, and Enamine. Finally a total of 20 compounds were selected from the top ranking compounds, and shifted to the subsequent in vitro and in vivo studies, which results will be reported in the near future.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, China.
authors.forename: Guo-Bo
authors.initials: GB
authors.lastname: Li
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Yang
authors.forename: Shan
authors.initials: S
authors.lastname: Feng
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Zhou
authors.forename: Qi
authors.initials: Q
authors.lastname: Huang
authors.forename: Huan-Zhang
authors.initials: HZ
authors.lastname: Xie
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Li
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D055808:Drug Discovery; D008956:Models, Chemical; D008958:Models, Molecular; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
chemical_list: D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1