| 分子模拟方法研究四氢化吡啶并[1,2-a]吲哚酮衍生物对GSK3β和CDK5的选择性 |
| Exploring the Selectivity of Tetrahydropyrido[1,2-a]isoindolone Derivatives to GSK3β and CDK5 by Computational Methods |
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| 摘要: 本文通过分子对接，分子动力学模拟（MD）和MM/PBSA能量计算的方法，从分子水平研究了3个四氢化吡啶并[1，2-a]吲哚酮衍生物与CDK5和GSK3β的相互作用，并揭示了这些抑制剂对GSK3β的选择性抑制机理。分子对接结果表明，抑制剂对2种激酶具有相似的结合模式，结合口袋处的残基也都根据晶体结构的序列比对相互对应。研究体系的RMSD随时间的稳定变化，表明模拟体系已达到稳定状态，因而后续的分析是可靠的。CDK5/抑制剂体系，RMSD在0.15 nm上下波动，CDK5/M1和CDK5/M2骨架轻微波动，稍高于CDK5/M3；而GSK3β体系的RMSD值略高于CDK5体系，在0.17 nm上下波动，GSK3β/M1和GSK3ββ/M2的骨架波动平衡值则稍低于GSK3β/M3。活性较大的抑制剂增强了蛋白骨架整体的“柔性”，即对激酶构象产生一定影响。能量分析表明，静电能和范德华作用能够区分不同抑制剂对同种激酶的生物活性差异。极性溶剂化自由能对区分抑制剂选择性也很重要，残基分解表明GSK3β的Glu97、Thr138是造成抑制剂选择性的主要原因。抑制剂与CDK5和GSK3β结合的过程中，蛋白质残基的动态相关性存在差异，铰链区域的Thr138与Val135~Gln206区域残基正相关，证实Thr138残基是区分抑制剂选择性的关键。 |
| 关键词: 四氢化吡啶并[1,2-a]吲哚酮衍生物 分子动力学模拟 选择性 稳定性 |
| 基金项目: 国家自然科学基金（No.20706029，20876073，91434109）资助项目。 |
| Abstract: Tetrahydropyrido[1,2-a]isoindolone derivatives are potent inhibitors of glycogen synthase kinase 3β (GSK3β) instead of homologous cyclin-dependent kinase 5 (CDK5). Molecular docking, molecular dynamics simulation, and MM/PBSA energy calculation are utilized to reveal the kinase inhibitors' selective mechanism at the molecular level for improving selectivity. Dynamic cross-correlation map (DCCM) analysis is applied to study the effect of the inhibitor on the interactions between each residue in CDK5 and GSK3β. The results of molecular docking indicate that the binding modes of three inhibitors with two kinases are especially similar, and residues in the binding pockets of two kinases are aligned with each other based on the sequence comparing analysis of crystal structures. The analysis of Root Mean Square Deviation (RMSD) with little fluctuation underlies the stability and reliability of systems. Its values of CDK5 (~0.15 nm) are less than GSK3β (~0.17 nm), and the inhibitor with higher value holds stronger flexibility and conformational changes of kinases. In terms of energies, the electrostatic and van der Walls energies are the major interactions for differentiating the activity between the same inhibitor and two kinases. And the polar solvation energy plays pivotal role in discriminating the selectivity of kinase inhibitor. The residue decomposition indicates that the residues Glu97 and Thr138 of GSK3β are the key residues for differentiating the inhibitor selectivity. On the other hand, in the aspect of inter-residue interaction in one kinase, results indicate that the dynamic correlation of residues is different during the binding process of CDK5 and GSK3β with inhibitors. The correlation of Thr138 in the hinge domain of GSK3β with that of residues Val135~Gln206 is positive, while the correlation of Gln85 and Cys83~Ala150 in CDK5 is unclear, which is a key factor to distinguish inhibitor selectivity. |
| Keywords: tetrahydropyrido[1,2-a]isoindolone derivatives molecular dynamics simulation selectivity stability |
| 投稿时间：2016-05-11 修订日期：2016-09-12 |
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| 董珂珂,杨雪雨,赵腾腾,朱小蕾.分子模拟方法研究四氢化吡啶并[1,2-a]吲哚酮衍生物对GSK3β和CDK5的选择性[J].无机化学学报,2016,32(11):1919-1930. |
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