Structural basis of valmerins as dual inhibitors of GSK3β/CDK5
Structural basis of valmerins as dual inhibitors of GSK3β/CDK5
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valmerins 作为 GSK3β/CDK5 双重抑制剂的结构基础
DOI：
10.1007/s00894-014-2407-1
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发表时间：
2014-09-01
影响因子：
2.2
通讯作者：
Lu, Shaoyong
中科院分区：
文献类型：
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作者：
Li, Xiaolong;Wang, Xiaowei;Lu, Shaoyong
在蛋白激酶抑制剂的发现中，多靶点药物的开发正变得越来越有吸引力。本研究通过分子对接、分子动力学模拟、分子力学泊松-玻尔兹曼表面积（MM-PBSA）结合自由能计算、主成分分析（PCA）和动态相互关联矩阵（DCCM）等方法，探讨了valmerin-19作为糖原合酶激酶3 β (GSK3 β)和细胞周期蛋白依赖性激酶5 （CDK5）双重抑制剂的分子机制。详细的MM-PBSA计算显示，valmerin-19与GSK3 β /CDK5的结合自由能分别为-12.60 +/- 2.28 kcal mol（-1）和-11.85 +/- 2.54 kcal mol(-1)，表明valmerin-19具有GSK3 β /CDK5的双重抑制剂作用。PCA和DCCM分析结果表明，valmerin-19与GSK3 β /CDK5的结合降低了GSK3 β /CDK5的构象动力学，valmerin-19与GSK3 β /CDK5的结合可能主要通过构象选择机制发生。这项研究可能有助于未来设计新的和有效的双重GSK3 β /CDK5抑制剂。
Development of multi-target drugs is becoming increasingly attractive in the repertoire of protein kinase inhibitors discovery. In this study, we carried out molecular docking, molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations, principal component analysis (PCA), and dynamical cross-correlation matrices (DCCM) to dissect the molecular mechanism for the valmerin-19 acting as a dual inhibitor for glycogen synthase kinase 3 beta (GSK3 beta) and cyclin-dependent kinase 5 (CDK5). Detailed MM-PBSA calculations revealed that the binding free energies of the valmerin-19 to GSK3 beta/CDK5 were calculated to be -12.60 +/- 2.28 kcal mol(-1) and -11.85 +/- 2.54 kcal mol(-1), respectively, indicating that valmerin-19 has the potential to act as a dual inhibitor of GSK3 beta/CDK5. The analyses of PCA and DCCM results unraveled that binding of the valmerin-19 reduced the conformational dynamics of GSK3 beta/CDK5 and the valmerin-19 bound to GSK3 beta/CDK5 might occur mostly through a conformational selection mechanism. This study may be helpful for the future design of novel and potent dual GSK3 beta/CDK5 inhibitors.