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Determination of structural requirements of Mer kinase inhibitors and binding interaction analysis using in silico approaches

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Abstract

Mer kinase is implicated as therapeutic target for the prevention and treatment of thrombosis. A molecular modeling study was performed on a series of pyrimidine-based inhibitors of Mer specific tyrosine kinase. The relationship between the structure and the activity of these inhibitors was studied using three-dimensional quantitative structure-activity relationship, molecular docking and molecular dynamics simulations. A reliable comparative molecular similarity indices analysis model with a cross-validated correlation coefficient (q 2) of 0.637 and a conventional correlation coefficient (r 2) of 0.955 was obtained from the combination of steric and hydrogen bond donor fields. Model showed acceptable predictive capability with predicted correlation coefficient (r 2 pred) of 0.614. Satisfactory performance in several validation procedures indicated the reliability and robustness of the model. Docking study was performed to determine the binding mode of these inhibitors inside the active site of Mer kinase. Molecular dynamics simulation was performed on the docked structure to explore the thorough binding process. Docking and molecular dynamics simulation identified some crucial binding residues such Leu593, Pro672, Phe673, Met674, Gly677, Asp678, Thr681, Tyr685, and Met730. This study provides useful information for the design of novel and more potent antithrombotic agents.

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Acknowledgments

This work was supported by the National Research Foundation of Korea grant (MRC, 2015-009070) funded by the Korea government (MSIP).

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Authors and Affiliations

  1. Department of Biomedical Sciences, College of Medicine, Chosun University, Gwangju, 501-759, Republic of Korea

    Anand Balupuri, Pavithra K. Balasubramanian & Seung Joo Cho

  2. Department of Cellular and Molecular Medicine, College of Medicine, Chosun University, Gwangju, 501-759, Republic of Korea

    Seung Joo Cho

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  1. Anand Balupuri
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Correspondence to Seung Joo Cho.

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Balupuri, A., Balasubramanian, P.K. & Cho, S.J. Determination of structural requirements of Mer kinase inhibitors and binding interaction analysis using in silico approaches. Med Chem Res 25, 3021–3029 (2016). https://doi.org/10.1007/s00044-016-1722-8

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