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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

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Abstract

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.

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Acknowledgments

The authors are grateful for the support of the National Science Foundation of China (30901743), the National Key Program of China (2012ZX09103101-022), the State Key Laboratory of Drug Research, and Doctoral Fund of Ministry of Education.

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Authors and Affiliations

  1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of China

    Hao Luo, Lufei Lu, Feng Wu, Meng Zhou, Xueyan Hou, Wenjuan Zhang, Zhengyu Ding & Rui Li

  2. Department of Pharmacy, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu, 610072, Sichuan, People’s Republic of China

    Jianyou Shi

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  1. Hao Luo
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Correspondence to Rui Li.

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Hao Luo and Jianyou Shi have contributed equally to this study.

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Luo, H., Shi, J., Lu, L. et al. 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. Med Chem Res 23, 747–758 (2014). https://doi.org/10.1007/s00044-013-0665-6

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