白藜芦醇衍生物作为新型LSD1/HDAC双靶点抑制剂的计算模拟研究

Resveratrol derivatives as novel LSD1/HDAC dual inhibitors by using the computer simulations

本研究选择前期设计出来的6个白藜芦醇衍生物LSD1抑制剂R1~R6,通过分子对接、分子动力学模拟、分子力学/广义玻恩表面积(MM/GBSA)等计算模拟方法探索了这些衍生物与HDAC8的相互作用模式以及结合自由能。以HDAC8的共晶配体CRA-A作为参考,结果显示,白藜芦醇衍生物R1~R6均能以双齿配位的形式与Zn^(2+)结合,与HDAC8有效结合。在分子动力学模拟的过程中,小分子的羟肟酸基团的两个氧原子始终与Zn^(2+)双齿配位,且6个白藜芦醇衍生物始终在HDAC8的疏水腔内。R1~R6与HDAC8的结合自由能计算结果表明,R1和R3与HDAC8的结合能力最强(分别为-200.00 kcal·mol^(-1)和-202.62 kcal·mol^(-1)),和其与LSD1的结合能力一致。其中,静电相互作用是主要的稳定因素。能量分解结果揭示ASP164、ASP253和HIS166是小分子与HDAC8结合过程中的关键氨基酸。

In this study,six resveratrol derivatives LSD1 inhibitors R1~R6 were selected and the interaction mode and binding free energies between these derivatives and HDAC8 were explored using molecular docking,molecular dynamics simulation,molecular mechanics/generalized bone surface area(MM/GBSA) and a series of computational simulation methods.Using the crystalline ligand of HDAC8(CRA-A) as a reference,it shown that all resveratrol derivatives R1~R6 could bind Zn^(2+)ion of HDAC8 in a bidentate coordination form.This indicates that the six derivatives can bind HDAC8 efficiently.Meanwhile during the molecular dynamics simulation,the two oxygen atoms of the hydroxamic acid group of the small molecule were coordinated with the Zn^(2+)bidentate and the six derivatives located in the hydrophobic cavity of HDAC8 all the time.The free energy calculation between HDAC8 and R1~R6 suggested that R1 and R3 had the strongest binding ability to HDAC8(-200.00 kcal·mol^(-1) and-202.62 kcal·mol^(-1),respectively),which was consistent with their binding ability to LSD1.The electrostatic interaction stands out as the primary stabilizing factor among them.Energy decomposition results revealed that ASP164,ASP253 and HIS166 are key amino acids in the binding of HDAC8 to small molecules.