Binding Selectivity Analysis of AURKs Inhibitors through Molecular Dynamics Simulation Studies - Raw Data

Aurora kinases (AURKs) have been identified as promising biological targets for the treatment of cancer. In this study, molecular dynamics simulations were employed to investigate the binding selectivity of three inhibitors (HPM, MPY, and VX6) towards AURKA and AURKB by predicting their binding free energies. The results show that the inhibitors HPM, MPY, and VX6 have more favorable interactions with AURKB as compared to AURKA. The binding energy decomposition analysis revealed that four common residue pairs (L139, L83), (V147, V91), (L210, L154), and (L263, L207) showed significant binding energies with HPM, MPY, and VX6, hence responsible for the binding selectivity of AURKA and AURKB to the inhibitors. The MD trajectory analysis also revealed that the inhibitors affect the dynamic flexibility of protein structure, which is also responsible for the partial selectivity of HPM, MPY, and VX6 towards AURKA and AURKB. As expected, this study provides useful insights for the design of potential inhibitors with high selectivity for AURKA and AURKB.

极光激酶（Aurora kinases, AURKs）已被确定为极具潜力的癌症治疗生物学靶点。本研究采用分子动力学模拟，通过预测结合自由能，探究了三种抑制剂（HPM、MPY及VX6）对极光激酶A（AURKA）与极光激酶B（AURKB）的结合选择性。结果表明，相较于AURKA，HPM、MPY与VX6这三种抑制剂与AURKB之间的相互作用更为有利。结合能分解分析显示，四组共有的残基对[(L139, L83)、(V147, V91)、(L210, L154)及(L263, L207)]与HPM、MPY、VX6均存在显著结合能，因此是AURKA与AURKB对这三种抑制剂产生结合选择性的关键因素。分子动力学轨迹分析还显示，该三类抑制剂会影响蛋白质结构的动态柔性，这也是HPM、MPY与VX6对AURKA和AURKB产生部分选择性的重要原因。正如预期，本研究为设计对AURKA与AURKB具有高选择性的潜在抑制剂提供了极具价值的理论参考。