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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Authors: | Yuanhua?Cheng Wei?Cui Quan?Chen Chen-Ho?Tung Email author" target="_blank">Mingjuan?JiEmail author Email author" target="_blank">Fushi?ZhangEmail author |
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Institution: | (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;(2) College of Chemistry and Chemical Engineering, Graduate University of Chinese Academy of Sciences, 100049 Beijing, People’s Republic of China; |
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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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