title: Fragment virtual screening based on Bayesian categorization for discovering novel VEGFR-2 scaffolds.
abstract: The discovery of novel scaffolds against a specific target has long been one of the most significant but challengeable goals in discovering lead compounds. A scaffold that binds in important regions of the active pocket is more favorable as a starting point because scaffolds generally possess greater optimization possibilities. However, due to the lack of sufficient chemical space diversity of the databases and the ineffectiveness of the screening methods, it still remains a great challenge to discover novel active scaffolds. Since the strengths and weaknesses of both fragment-based drug design and traditional virtual screening (VS), we proposed a fragment VS concept based on Bayesian categorization for the discovery of novel scaffolds. This work investigated the proposal through an application on VEGFR-2 target. Firstly, scaffold and structural diversity of chemical space for 10 compound databases were explicitly evaluated. Simultaneously, a robust Bayesian classification model was constructed for screening not only compound databases but also their corresponding fragment databases. Although analysis of the scaffold diversity demonstrated a very unevenly distribution of scaffolds over molecules, results showed that our Bayesian model behaved better in screening fragments than molecules. Through a literature retrospective research, several generated fragments with relatively high Bayesian scores indeed exhibit VEGFR-2 biological activity, which strongly proved the effectiveness of fragment VS based on Bayesian categorization models. This investigation of Bayesian-based fragment VS can further emphasize the necessity for enrichment of compound databases employed in lead discovery by amplifying the diversity of databases with novel structures.
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
authors.forename: Haichun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Ran
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
authors.forename: Jinxing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Lu
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
authors.forename: Anyang
authors.initials: A
authors.lastname: Xu
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Pan
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Qiao
authors.affiliation: School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China. lutao@cpu.edu.cn.|School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China. lutao@cpu.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China. ydchen@cpu.edu.cn.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Chen
mesh_terms: D001499:Bayes Theorem; D019295:Computational Biology / Q000379:methods*; D062126:Databases, Chemical; D016208:Databases, Factual; D055808:Drug Discovery; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D010446:Peptide Fragments; D051497:Receptor, Fibroblast Growth Factor, Type 2
keywords: Bayesian categorization; Fragment; Scaffold diversity; VEGFR-2; Virtual screening