N-取代马来酰亚胺类hMGL抑制剂的3D-QSAR、分子对接和分子动力学研究  

Study on 3D QSAR,Molecular Docking and Dynamics Simulations of N-substituted Maleimide Derivatives as hMGL Inhibitors

作　　者：梁婷婷 张璐 闫超群[2] 范玉柱 梁泰刚[2] Liang Tingting;Zhang Lu;Yan Chaoqun;Fan Yuzhu;Liang Taigang(Shanxi Provincial Hospital of Traditional Chinese Medicine,Taiyuan,030012;School of Pharmaceutical Science,Shanxi Medical University,Jinzhong,030600)

机构地区：[1]山西省中医院,太原030012 [2]山西医科大学药学院,晋中030600

出　　处：《化学通报》2024年第7期872-881,769,共11页Chemistry

基　　金：山西省基础研究计划项目(20210302123300);山西省“黄芪”资源产业化与产业国际化协同创新中心项目(HQXTCXZXX2016-021);山西省“1331工程”创新团队建设项目(2018-4培育No.11);山西省自然科学基金项目(201601D011112);国家重点研发计划项目(2019YFC1710803)资助。

摘　　要：本文通过三维定量构效关系(3D-QSAR)建模、分子对接和分子动力学模拟,探讨了41个N-取代马来酰亚胺类衍生物与人单酰甘油脂肪酶(hMGL)的相互作用,并构建了相关模型。其中,比较分子力场分析模型(CoMFA、q^(2)=0.541、r^(2)=0.972)和比较分子相似性指数分析模型(CoMSIA、q^(2)=0.588、r^(2)=0.919)具有较好的预测能力。QSAR模型等势图阐明了该系列化合物生物活性与结构的关系,并依此设计了系列衍生物。采用分子对接和分子动力学模拟探讨了高活性化合物36、46与hMGL(PDB ID:3PE6)的结合模式和稳定性,结果表明二者主要通过氢键和疏水相互作用与hMGL结合并且形成了稳定的复合物。随后对pIC_(50)预测值优于文献报道中最高活性化合物36的8个衍生物进行分子对接和ADMET预测,选择2个衍生物进行分子动力学模拟,结果表明2个衍生物分别与hMGL形成的复合物结合构象稳定。本研究为新型N-取代马来酰亚胺类hMGL抑制剂的开发提供了理论依据。The interactions between N-substituted maleimide derivatives and human monoglyceride lipase(hMGL)were investigated using 3D quantitative structure-activity relationship(3D-QSAR)modeling,molecular docking,and molecular dynamics simulations.The resulting models,comparative molecular field analysis(CoMFA,q^(2)=0.541,r^(2)=0.972)and comparative molecular similarity index analysis(CoMSIA,q^(2)=0.588,r^(2)=0.919),exhibited a high level of predictive accuracy.The contour maps generated by the QSAR models provided insights into the correlation between the chemical structure of N-substituted maleimide derivatives and their biological activity.Based on these insights,40 derivatives were designed accordingly.Additionally,molecular docking and molecular dynamics simulations were employed to investigate the binding mode and stability of the potent compounds 36 and 46 with hMGL(PDB ID:3PE6).The findings indicated that both compounds primarily interact with hMGL through hydrogen bonding and hydrophobic interactions,leading to the formation of stable complexes.Subsequently,molecular docking and ADMET prediction were conducted for 8 derivatives with predicted pIC_(50) values higher than the pIC_(50) value of the most active compound 36.Two derivatives were selected for molecular dynamics simulations,and the results indicated that the complexes formed by two derivatives with hMGL were conformationally stable.These research results provide a theoretical basis for the development of powerful N-substituted maleimide derivatives as hMGL inhibitors.

关 键 词：N-取代马来酰亚胺类衍生物 人单酰甘油脂肪酶 3D-QSAR 分子对接 分子动力学 

分 类 号：TQ460.1[化学工程—制药化工]