title: Structural determinants of CX-4945 derivatives as protein kinase CK2 inhibitors: a computational study.
abstract: Protein kinase CK2, also known as casein kinase-2, is involved in a broad range of physiological events including cell growth, proliferation and suppression of apoptosis which are related to human cancers. A series of compounds were identified as CK2 inhibitors and their inhibitory activities varied depending on their structures. In order to explore the structure-activity correlation of CX-4945 derivatives as inhibitors of CK2, in the present study, a set of ligand- and receptor-based 3D-QSAR models were developed employing Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA). The optimum CoMFA (R(cv) (2) = 0.618, R(pred) (2) = 0.892) and CoMSIA (R(cv) (2) = 0.681, R(pred) (2) = 0.843) models exhibited reasonable statistical characteristics for CX-4945 derivatives. The results indicated that electrostatic effects contributed the most to both CoMFA and CoMSIA models. The combination of docking analysis and molecular dynamics (MD) simulation showed that Leu45, Lys68, Glu81, Val116, Asp175 and Trp176 of CK2 which formed several direct or water-bridged H-bonds with CX-4945 are crucial for CX-4945 derivatives recognition to CK2. These results can offer useful theoretical references for designing more potent CK2 inhibitors.
authors.affiliation: Chemistry and Chemical Engineering School, Northeast Petroleum University, Daqing 163000, China; E-Mails:  dqliuhongbo@126.com  (H.L.);  mrwj@nepu.edu.cn  (J.W.).
authors.forename: Hongbo
authors.initials: H
authors.lastname: Liu
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Jinghui
authors.initials: J
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Guohui
authors.initials: G
authors.lastname: Li
mesh_terms: D001665:Binding Sites; D047390:Casein Kinase II / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009287:Naphthyridines / Q000737:chemistry* / Q000378:metabolism; D010619:Phenazines; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship
chemical_list: D009287:Naphthyridines; D010619:Phenazines; D047428:Protein Kinase Inhibitors; C555142:silmitasertib; D047390:Casein Kinase II
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