title: An efficient multistep ligand-based virtual screening approach for GPR40 agonists.
abstract: G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFAR1) is a member of the GPCR superfamily, and GPR40 agonists have therapeutic potential for type 2 diabetes. With the crystal structure of GPR40 currently unavailable, various ligand-based virtual screening approaches can be applied to identify novel agonists of GPR40. It is known that each ligand-based method has its own advantages and limitations. To improve the efficiency of individual ligand-based methods, an efficient multistep ligand-based virtual screening approach is presented in this study, including the pharmacophore-based screening, physicochemical property filtering, protein-ligand interaction fingerprint similarity analysis, and 2D-fingerprint structural similarity search. A focused decoy library was generated and used to evaluate the efficiency of this virtual screening protocol. This multistep workflow not only significantly improved the hit rate compared with each individual ligand-based method, but also identified diverse known actives from decoys. This protocol may serve as an efficient virtual screening tool for the targets without crystal structures available to discover novel active compounds.
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Basic Science, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
authors.forename: Sihui
authors.initials: S
authors.lastname: Yao
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.forename: Zifan
authors.initials: Z
authors.lastname: Zhou
authors.forename: Haichun
authors.initials: H
authors.lastname: Liu
authors.forename: Haoliang
authors.initials: H
authors.lastname: Yuan
authors.forename: Ting
authors.initials: T
authors.lastname: Ran
authors.forename: Shuai
authors.initials: S
authors.lastname: Lu
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Ke
authors.forename: Jinxing
authors.initials: J
authors.lastname: Xu
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiong
authors.forename: Yadong
authors.initials: Y
authors.lastname: Chen
mesh_terms: D055598:Chemical Phenomena; D062313:Databases, Pharmaceutical; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D014584:User-Computer Interface
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled