TNK-651和GS-9137融合型HIV-1RT(NNRTI)/IN双靶点抑制剂的分子作用机制研究  

Molecular mechanism of dual HIV-1 RT(NNRTI)/IN inhibitors fused by TNK-651 and GS-9137

作　　者：康家雄 朱江[2] 李爱秀[1,3] 肖泽云 李凯[1,4] KANG Jia-xiong;ZHU Jiang;LI Ai-xiu;XIAO Ze-yun;LI Kai(Drug Design Laboratory,Logistics University of PAP,Tianjin 300309,China)

机构地区：[1]武警后勤学院基础部药物设计实验室,天津300309 [2]武警后勤学院卫勤系,天津300309 [3]天津市职业与环境危害防制重点实验室,天津300309 [4]武警山西总队医院药剂科,山西太原030006

出　　处：《武警后勤学院学报（医学版）》2018年第7期558-565,共8页Journal of Logistics University of PAP（Medical Sciences）

基　　金：国家自然科学基金项目(81241114);天津市科技攻关计划重点科技攻关专项基金资助项目(06YFGZSH07000);武警后勤学院研究生创新课题项目(WHYC201605)

摘　　要：【目的】揭示6-苄基-1-[(苄氧基)甲基)]-5-异丙基尿嘧啶(6-benzyl-1-[(benzyloxy)methyl]-5-isopropyluracil,TNK-651)和埃替格韦(elvitegravir,GS-9137)融合型Ⅰ型人类免疫缺陷病毒(human immunodeficiency virus type 1,HIV-1)逆转录酶(reverse transcriptase,RT)的非核苷类抑制剂(non-nucleoside RT inhibitors,NNRTIs)作用位点和整合酶(integrase,IN)活性位点的双靶点抑制剂RT(NNRTI)/IN与RT和IN的结合模式及分子作用机制。【方法】分别对选取的7个RT、11个IN复合物晶体结构中的底物分子进行相似性分析;综合运用自身对接和交叉对接方法分别从中优选出RT和IN的最佳受体结构模型;基于分子对接技术分别建立RT、IN与抑制剂的结合模型,据此阐明抑制剂的作用机制。【结果】对接结果显示,TNK-651和GS-9137融合型HIV-1 RT(NNRTI)/IN双靶点抑制剂结合于RT的NNRTIs结合位点,与其形成氢键作用、π-π堆积作用、阳离子-π作用、疏水相互作用;结合于IN的IN-DNA界面活性位点,与其形成氢键作用、π-π堆积作用、疏水相互作用、金属离子螯合作用。【结论】TNK-651和GS-9137融合型HIV-1 RT(NNRTI)/IN双靶点抑制剂通过与RT的Lys101和Tyr188形成关键的氢键作用和π-π堆积作用,与IN的Asp128、Asp185、Glu221及Mg^(2+)和高度疏水性亚结合口袋形成关键的金属离子螯合作用和强疏水相互作用,发挥抗RT和IN双重活性。【Objective】To reveal the binding modes and molecular mechanism on dual HIV-1 RT(NNRTI)/IN inhibitors fused by 6-benzyl-1-[(benzyloxy)methyl)]-5-isopropyluracil(TNK-651) and elvitegravir(GS-9137), which simultaneously targeted nonnucleoside reverse transcriptase(RT) inhibitors binding pocket of RT and active site of integrase(IN).【Methods】The similarity analysis was performed on the substrate molecules in the selected complex crystal structures of 7 RTs and 11 INs, respectively. The optimal receptor structure model of RT and IN was preferred through jointly using the self-docking and cross-docking methods,respectively. The ligand-receptor docking complexes were constructed via molecular docking, and the action mechanism of the inhibitors was elucidated.【Results】The docking results indicated that dual HIV-1 RT(NNRTI)/IN inhibitors fused by TNK-651 and GS-9137 were embedded in NNRTIs binding site of RT, forming hydrogen bond, π-π stacking interaction, cation-π interaction and hydrophobic interaction, and were bound to the IN-DNA interface active site of IN, establishing hydrogen bond, π-π stacking interaction, hydrophobic interaction and metal ion chelation.【Conclusion】 Dual HIV-1 RT(NNRTI)/IN inhibitors fused by TNK-651 and GS-9137 exert dual activities against RT and IN via forming key hydrogen bond and π-π stacking interaction with Lys101 and Tyr188 in RT, respectively, and key metal ion chelation and strong hydrophobic interaction with Asp128, Asp185, Glu221, Mg2+ and highly hydrophobic subpocket, respectively.

关 键 词：TNK-651和GS-9137融合型 双靶点抑制剂 分子对接 分子机制 

分 类 号：R914[医药卫生—药物化学]