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The molecular mechanism studies of chirality effect of PHA-739358 on Aurora kinase A by molecular dynamics simulation and free energy calculations

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Abstract

Aurora kinase family is one of the emerging targets in oncology drug discovery and several small molecules targeting aurora kinases have been discovered and evaluated under early phase I/II trials. Among them, PHA-739358 (compound 1r) is a 3-aminopyrazole derivative with strong activity against Aurora A under early phase II trial. Inhibitory potency of compound 1r (the benzylic substituent at the pro-R position) is 30 times over that of compound 1s (the benzylic substituent at the pro-S position). In present study, the mechanism of how different configurations influence the binding affinity was investigated using molecular dynamics (MD) simulations, free energy calculations and free energy decomposition analysis. The predicted binding free energies of these two complexes are consistent with the experimental data. The analysis of the individual energy terms indicates that although the van der Waals contribution is important for distinguishing the binding affinities of these two inhibitors, the electrostatic contribution plays a more crucial role in that. Moreover, it is observed that different configurations of the benzylic substituent could form different binding patterns with protein, thus leading to variant inhibitory potency of compounds 1r and 1s. The combination of different molecular modeling techniques is an efficient way to interpret the chirality effects of inhibitors and our work gives valuable information for the chiral drug design in the near future.

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Acknowledgments

The project was supported by the National Science and Technology Major Special Project of China (No. 2009ZX09501-011) and the Natural Science Foundation of China (No. 21073105).

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Authors and Affiliations

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

    Yuanhua Cheng, Chen-Ho Tung & Fushi Zhang

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

    Wei Cui, Quan Chen & Mingjuan Ji

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  1. Yuanhua Cheng
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  2. Wei Cui
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  3. Quan Chen
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  4. Chen-Ho Tung
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Correspondence to Mingjuan Ji or Fushi Zhang.

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Cheng, Y., Cui, W., Chen, Q. et al. The molecular mechanism studies of chirality effect of PHA-739358 on Aurora kinase A by molecular dynamics simulation and free energy calculations. J Comput Aided Mol Des 25, 171–180 (2011). https://doi.org/10.1007/s10822-010-9408-7

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