Mechanistic Insights into the Mechanism of Inhibitor Selectivity toward the Dark Kinase STK17B against Its High Homology STK17A.
Mechanistic Insights into the Mechanism of Inhibitor Selectivity toward the Dark Kinase STK17B against Its High Homology STK17A.
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对抑制剂选择性的机理对深色激酶STK17B对其高同源性STK17A的机制。
DOI：
10.3390/molecules27144655
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发表时间：
2022-07-21
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影响因子：
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STK17B作为死亡相关蛋白激酶（death-associated protein kinase， DAPK）家族成员，在细胞凋亡调控中发挥重要作用，被认为是治疗肝细胞癌的一个有前景的药物靶点。然而，蛋白激酶高度保守的atp结合位点对设计针对特定DAPK异构体的选择性抑制剂提出了挑战。本研究通过分子对接、多次大尺度分子动力学（MD）模拟和结合自由能计算等方法，揭示PKIS43对STK17B选择性结合的分子机制，以对抗其高度同源的STK17A。MD模拟结果显示，与STK17B相比，STK17A的激活环有明显的构象排列。结合自由能预测表明，控制PKIS43结合选择性的驱动力来自于蛋白质与配体静电相互作用的差异。此外，每残基自由能分解揭示了Arg41在STK17B的磷酸盐结合环上的能量贡献是PKIS43结合特异性的决定因素。本研究可为合理设计新型有效的STK17B选择性抑制剂提供有用信息。
As a member of the death-associated protein kinase (DAPK) family, STK17B plays an important role in the regulation of cellular apoptosis and has been considered as a promising drug target for hepatocellular carcinoma. However, the highly conserved ATP-binding site of protein kinases represents a challenge to design selective inhibitors for a specific DAPK isoform. In this study, molecular docking, multiple large-scale molecular dynamics (MD) simulations, and binding free energy calculations were performed to decipher the molecular mechanism of the binding selectivity of PKIS43 toward STK17B against its high homology STK17A. MD simulations revealed that STK17A underwent a significant conformational arrangement of the activation loop compared to STK17B. The binding free energy predictions suggested that the driving force to control the binding selectivity of PKIS43 was derived from the difference in the protein–ligand electrostatic interactions. Furthermore, the per-residue free energy decomposition unveiled that the energy contribution from Arg41 at the phosphate-binding loop of STK17B was the determinant factor responsible for the binding specificity of PKIS43. This study may provide useful information for the rational design of novel and potent selective inhibitors toward STK17B.
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