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Studying the mechanism that enables paullones to selectively inhibit glycogen synthase kinase 3 rather than cyclin-dependent kinase 5 by molecular dynamics simulations and free-energy calculations

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Abstract

Glycogen synthase kinase 3 (GSK-3) is an attractive target for the treatment of diabetes, and paullones have been reported to be effective inhibitors of GSK-3. However, it is still a challenging task to improve selectivity among protein kinases, especially cyclin-dependent kinases (CDKs). Here we investigated the mechanism that enables paullones to selectively inhibit GSK-3 rather than cyclin-dependent kinase 5 (CDK5) using sequence alignment, molecular dynamics simulations, free-energy calculations and free-energy decomposition analysis. The results indicate that the interaction between paullones and Val135 of GSK-3 is obviously stronger than that between paullones and Cys83 of CDK5, suggesting that paullones could be utilized as potent selective inhibitors. Meanwhile, we observed that the decrease in the interaction between paullones and the Asp86 of CDK5 favors their selectivity towards GSK-3 rather than CDK5, as demonstrated using 1-azakenpaullone as an example. Although substitution at position 9 and replacement at position 2 may influence the activity of GSK-3, they only have a minor effect on the selectivity. We expect that the information obtained here could prove useful for developing specific paullone inhibitors of GSK-3.

Glycogen synthase kinase-3 is an attractive target for the treatment of diabetes and paullones have been reported to be effective inhibitors of GSK-3. However, how to improve the selectivity among protein kinases is still a challenging task, especially with the cyclin-dependent kinases. Here we investigated the mechanism that enables paullones to selectively inhibit GSK-3 rather than cyclin-dependent kinase 5 (CDK5) using sequence alignment, molecular dynamics simulations, free energy calculations and free energy decomposition analysis

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Acknowledgments

The project was supported by the National Science and Technology Major Special Project of China (No. 2009ZX09501-011).

We thank Prof. Xiaojie Xu at the Department of Chemistry of Peking University for providing access to computer software such as AMBER.

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Authors and Affiliations

  1. College of Chemistry and Chemical Engineering, Graduate University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China

    Quan Chen, Wei Cui & Mingjuan Ji

  2. Key Laboratory of Organic Optoelectronics and Molecular Engineering of Ministry of Education, Department of Chemistry, Tsinghua University, Beijing, 100084, People’s Republic of China

    Yuanhua Cheng & Fushi Zhang

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  1. Quan Chen
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  2. Wei Cui
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Correspondence to Mingjuan Ji.

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Chen, Q., Cui, W., Cheng, Y. et al. Studying the mechanism that enables paullones to selectively inhibit glycogen synthase kinase 3 rather than cyclin-dependent kinase 5 by molecular dynamics simulations and free-energy calculations. J Mol Model 17, 795–803 (2011). https://doi.org/10.1007/s00894-010-0762-0

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