PPAR α/γ双重激动剂的设计及分子动力学研究

Design and molecular dynamics simulations of novel dual agonists for treating type-2 diabetes by targeting peroxisome proliferator-activated receptors α/γ

目的:设计PPARα/γ双重激动剂,提高其降糖活性,为以后相关疾病的治疗提供科学的方法和依据。方法:应用Schrodinger Suite 2009中的Glide模块对drug-like数据库进行高通量虚拟筛选,对筛选出的结构利用"Core Hopping"模块进行修饰,利用Gromacs 4.0软件包进行分子动力学模拟研究,将PPARα/γ的空载蛋白及其与选出的配体小分子复合物体系分别进行10 ns的分子动力学模拟,最后应用Qikprop模块做ADME(吸收、分布、代谢、排泄)预测来推测这些化合物的成药可能性。结果:设计出一系列新的PPARα/γ双重激动剂。用分子对接方法和分子动力学模拟分析了新激动剂和PPARα/γ的相互作用机制,与临床应用的激动剂ragalitazar相比有更好的结合能力。通过ADME预测得出设计出的化合物均符合类药5原则。结论:通过计算机辅助设计得到的小分子与PPARα/γ的结合能力理论上优于激动剂ragalitazar。预期这些化合物可能成为新的治疗2型糖尿病的目标化合物。

Objective： To develop high active peroxisome proliferator-activated receptors α/γ novel dual agonists that would indicate the further research. Methods： In this study, the small molecule database of drug-like were high-throughput screened by Glide of Schrodinger Suite 2009, and the candidates were optimized by Core Hopping of Schrodinger Suite 2009. Then, the 10 ns MD simulation of PPAR protein with and without candidates were performed by software Gromacs 4.0. ADME was also carried out to check if those candidates hold the potential to become drug. Results： A novel class of PPAR dual agonists was discovered. It was observed by docking and molecular dynamics simulations that these novel agonists had more favorable conformation for binding to the two receptors than ragalitazar. It was predicted that the values for these novel candidates were all within the reasonable ranges. Conclusion： The binding affinity of the designed molecules is theoretically higher than the ragalitazar in PPARα/γ It is anticipated that the new agonists may become po- tential drug hits.