title: Identification of CK2 inhibitors with new scaffolds by a hybrid virtual screening approach based on Bayesian model; pharmacophore hypothesis and molecular docking.
abstract: Protein kinase casein kinase 2 (CK2), a member of the serine/threonine kinase family, has been established as one of the most attractive targets for molecularly targeted cancer therapy. The discovery of CK2 inhibitors has thus attracted much attention in recent years. In this investigation, a hybrid virtual screening approach based on Bayesian classification model, pharmacophore hypothesis and molecular docking was proposed and employed to identify CK2 inhibitors. We first established a naïve Bayes classification model of CK2 inhibitors/non-inhibitors and pharmacophore hypotheses of CK2 inhibitors. The docking parameters and scoring functions were also optimized in advance. The three virtual screening methods were sequentially used to screen two large chemical libraries, Specs and Enamine, for retrieving new CK2 inhibitors. Finally 30 compounds were selected from the final hits for in vitro CK2 kinase inhibitory assays. Five compounds with completely novel scaffolds showed a good inhibitory potency against CK2, which have good potentials for a future hit-to-lead optimization.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, No. 1, Keyuan 4 Road, High Tech Park, Chengdu, Sichuan 610041, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Di-wu
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Li
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Wang
authors.forename: Huan-Zhang
authors.initials: HZ
authors.lastname: Xie
authors.forename: Jiao
authors.initials: J
authors.lastname: Yang
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Zhang
authors.forename: Qi
authors.initials: Q
authors.lastname: Huang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.forename: Shan
authors.initials: S
authors.lastname: Feng
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D001499:Bayes Theorem; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D047390:Casein Kinase II