3D-QSAR Analysis on ATR Protein Kinase Inhibitors Using CoMFA and CoMSIA
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 (q2) of 0.752 and a
regression coefficient (r2) of 0.947. The CoMSIA models had a q2 of 0.728 and an r2 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.
Keywords: ATR inhibitor, 3D-QSAR, CoMFA, CoMSIA, docking, homology modeling, molecular design.
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