title: 3D-QSAR analysis on ATR protein kinase inhibitors using CoMFA and CoMSIA.
abstract: Ataxia telangiectasia-mutated and Rad3-related (ATR) protein kinase is an attractive anticancer target. In this study, comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) were performed on a series of aminopyrazine ATR inhibitors. The models generated by CoMFA had a cross-validated coefficient (q(2)) of 0.752 and a regression coefficient (r(2)) of 0.947. The CoMSIA models had a q(2) of 0.728 and an r(2) of 0.936. The reasonable quantitative structure-activity relationship model showed robust predictive ability. The contour map provided guidelines for building novel virtual compounds based on compound NO.40. In addition, the 3D structure of ATR was modeled by homology modeling. Molecular dynamic simulations were employed to optimize the structure. The docking results offered insights into the interactions between the inhibitors and the active site for potent analysis. This study provides useful guidance for the discovery of more potent compounds.
authors.forename: Xiurong
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China. sm7507@126.com.
authors.forename: Mao
authors.initials: M
authors.lastname: Shu
authors.forename: Yuanqiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Rui
authors.initials: R
authors.lastname: Yu
authors.forename: Shuang
authors.initials: S
authors.lastname: Yao
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Lin
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D020134:Catalytic Domain / Q000187:drug effects; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011719:Pyrazines; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins