Molecular dynamics-based self-organizing molecular field analysis on 3-amino-6-arylpyrazines as the ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibitors

The ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase is one of the apical regulators in the DNA damaging response signaling pathways. Inhibition of ATR kinase may greatly potentiates the cyto-toxicity by DNA damaging agents to the tumor cells while, have minimum effect on normal cells. In this article, the impact of ligand conformation on the three-dimensional quantitative structure–activity relationship (3D-QSAR) model of a series of 3-amino-6-arylpyrazines as ATR kinase inhibitors was investigated. We employed molecular dynamics (MDs) simulations to get the dynamic active conformations (DACs) of the compounds in the ATP-binding site of ATR kinase. As a result, the model based on the DACs extracted from the first nanosecond MD simulation is superior to that using static active conformations from docking with r 2 = 0.917; \(q_{\text{LOO}}^{2}\) = 0.880; standard error of estimate [SEE] = 0.259; F = 347.29; \(r_{\text{pred}}^{2}\) = 0.923; SEEpred = 0.301. Our results highlight the importance of incorporating DACs of ligand using MD simulation in 3D-QSAR studies. This study may also provide useful information to rationalize the design of novel ATR kinase inhibitors.