PPARα、γ、δ三靶点激动剂设计、虚拟筛选及分子动力学模拟研究

Design,virtual screening and molecular dynamics simulations of peroxisome proliferator activated receptor α,γ,δ pan agonists

目的:设计并筛选过氧化物酶体增殖物激活受体α、γ、δ(PPARα、γ、δ)三靶点激动剂,探讨其与三靶点相互作用情况。方法:根据PPARα、γ、δ三靶点激动剂2D药效团特征设计一系列小分子;通过分子对接方法对其进行虚拟筛选;应用分子动力学方法模拟其与PPARα、γ、δ的相互作用。结果:设计得到一系列苯氧乙酸类衍生物作为PPARα、γ、δ三靶点激动剂;对接结果表明通过柔性的连接基团连接一个芳香基团的苯氧乙酸类衍生物可以与PPARα、γ、δ活性位点良好结合;分子动力学结果表明模拟过程中受体与激动剂复合物体系是稳定的,苯氧乙酸类衍生物可以在PPAR配体结合位点灵活波动并与受体AF-2螺旋周期性地形成氢键,使AF-2螺旋稳定于激活构象从而引导协同因子与受体结合来激动受体启动转录过程。结论:通过柔性连接基团连接一个芳香基团的苯氧乙酸类衍生物可以作为PPARα、γ、δ三靶点激动剂。

Objective： To design and screen the peroxisome proliferator activated receptor α,γ,δ（PPARα,γ,δ） pan agonists and investigate the interaction between the agonists and receptors.Methods： A kind of small molecules were designed based on the 2D pharmacophoric features of PPAR pan agonists;virtual screening of the designed molecules was carried out through molecular docking;the interaction between designed molecules and the PPARs was performed by using molecular dynamics simulations.Results： Phenoxy acetic acid derivatives were designed as PPAR pan agonists.Docking results showed that phenoxy acetic acid derivatives with an aromatic tail group linked by a flexible spacer were found to dock well in the active sites of PPARs.Molecular dynamics simulations revealed that the receptor-agonist complexes remained stable during the simulations.Phenoxy acetic acid derivatives showed more flexibility in the ligand binding pockets of PPARs and could form hydrogen bonds with the AF-2 helix of PPARs periodically,which stabilized the AF-2 helix in an active conformation and directed the binding of the co-activators to the receptors to initiate the transcription process.Conclusion： Phenoxy acetic acid derivatives with an aromatic tail group linked by a flexible spacer can be recognized as PPAR pan agonists.