PI3K α/β选择性抑制剂的设计策略探析

Structural determinants of selective inhibitors towards PI3K α/β

目的研究PI3Kα/β选择性抑制剂设计策略。方法运用分子对接、分子动力学模拟、结合自由能计算和量子化学计算等方法分析PI3Kα/β选择性抑制剂与PI3Kα/β的结合方式。结果与结论亚型选择性抑制剂与PI3Kα/β结构之间的空间匹配和能量匹配存在差异,PI3Kα中Val851和PI3Kβ中Val848等残基对选择性产生影响。本研究为合理设计PI3Kα/β选择性抑制剂提供重要参考。

To explore the structural determinants of selective inhibitors towards PI3K α/β,the combinational computational approaches were carried out including molecular docking, molecular dynamics simulation, binding free energy calculation and quantum chemical calculation to analyze the binding mode of selective PI3K α/β inhibitors.The detailed different spatial matching and energy matching maps were figured out between PI3Kα and PI3Kβ.Pivotal amino acids, such as Val851 in PI3Kα and Val848 in PI3Kβ,significantly affected the selectivity mechanism.These findings will lead to broader coverage of PI3K α/β with target-specific inhibitors in a more rational point view.