结合QSAR、分子对接和动力学模拟剖析小分子与不同受体的结合亲和力

Analyzing the Affinity of Small Molecules with Different Receptors with QSAR,Molecular Docking and Molecular Dynamic Simulation

本文从三种不同的角度分析小分子与受体的结合情况,互相补充,为探讨不同类型结合模式提供有用的信息和研究手段。利用比较分子相似性指数法(CoMSIA)和分子全息定量构效关系法(HQSAR),建立一系列小分子与不同受体(AhR和TTR)亲和力活性数据的定量构效关系预测模型。结果表明模型均具有较高稳定性和预测能力(q^2>0.55,r^2>0.85)。同时,根据CoMSIA模型的等值线图和HQSAR模型的原子贡献图得出BDE154和BDE019与受体之间的结合作用方式,主要为疏水作用,带羟基基团化合物不利于与受体结合。此外,分子对接结果表明模型的结合力类型分别为疏水作用和π-π堆积作用。而分子动力学模拟的结果表明,随着小分子的加入,受体的二级结构发生转变。

Comparative molecular similarity indices analysis（CoMSIA）and hologram quantitative structureactivity relationship（HQSAR）were used to develop QSAR models and predict binding affinity among a series of small molecules and different receptors（AhR and TTR）.The internal validation results reveal that those developed models are robust and have high predictive capability（q2〉0.55,r2〉0.85）.Meanwhile,the hydrophobic interaction plays a main role in models between BDE154,BDE019 and receptors by the contour maps of CoMSIA and the atom contribution maps of HQSAR.Therefore,hydroxyl molecules have low binding capacity.Moreover,the results of docking model show that hydrophobic interactions andπ-πstacking effect are the major driving forces in the binding process.MD simulation show that the secondary structure of receptors are changed when ligands are added.In this paper,the binding models were analyzed with three different methods.And the results of these methods complement each other nicely.Our work provides useful techniques for studying different binding modes.