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
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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, Mg~(2+) and highly hydrophobic subpocket, respectively.
【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, Mg~(2+) and highly hydrophobic subpocket, respectively.
引文
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[25]Jasuja H,Chadha N,Kaur M,et al.Dual inhibitors of Janus kinase 2 and 3(JAK2/3):designing by pharmacophore-and docking-based virtual screening approach[J].Mol Divers,2014,18(2):253-267.
[26]Grawenhoff J,Engelman AN.Retroviral integrase protein and intasome nucleoprotein complex structures[J].World JBiol Chem,2017,8(1):32-44.
[27]Chen W,Zhan P,Wu JD,et al.The development of HEPTtype HIV non-nucleoside reverse transcriptase inhibitors and its implications for DABO family[J].Curr Pharm Des,2012,18(27):4165-4186.
[28]Zhang L,Tang XW,Cao YY,et al.Synthesis and biological evaluation of novel 2-arylalkylthio-5-iodine-6-substitutedbenzylpyrimidine-4(3H)-ones as potent HIV-1 non-nucleoside reverse transcriptase inhibitors[J].Molecules,2014,19(6):7104-7121.
[29]Zhan P,Chen X,Li D,et al.HIV-1 NNRTIs:structural diversity,pharmacophore similarity,and implications for drug design[J].Med Res Rev,2013,33(S1):E1-E72.
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[2]Yoshinaga T,Kobayashi M,Seki T,et al.Antiviral characteristics of GSK1265744,an HIV integrase inhibitor dosed orally or by long-acting injection[J].Antimicrob Agents Chemother,2015,59(1):397-406.
[3]Jones J,Taylor BS,Tieu HV,et al.CROI 2017:advances in antiretroviral therapy[J].Top Antivir Med,2017,25(2):51-67.
[4]肖泽云,李凯,李爱秀,等.新型HIV逆转录酶和整合酶双靶点抑制剂的虚拟筛选[J].中国医药导报,2017,14(27):4-7.
[5]康家雄,朱江,李爱秀,等.化学合成的HIV-1逆转录酶和整合酶双靶点抑制剂研究进展[J].武警后勤学院学报(医学版),2018,27(2):169-176.
[6]Manyeruke MH,Olomola TO,Majumder S,et al.Synthesis and evaluation of 3-hydroxy-3-phenylpropanoate esterAZT conjugates as potential dual-action HIV-1 integrase and reverse transcriptase inhibitors[J].Bioorg Med Chem,2015,23(24):7521-7528.
[7]Wang X,Zhang J,Huang Y,et al.Design,synthesis,and biological evaluation of 1-[(2-benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils as potent HIV-1 non-nucleoside reverse transcriptase inhibitors with an improved drug resistance profile[J].J Med Chem,2012,55(5):2242-2250.
[8]沈学彬,叶剑,杨立莉,等.HIV-1整合酶的功能及其抑制剂的研究进展[J].中国细胞生物学学报,2013,35(10):1514-1524.
[9]Wang Z,Vince R.Synthesis of pyrimidine and quinolone conjugates as a scaffold for dual inhibitors of HIV reverse transcriptase and integrase[J].Bioorg Med Chem Lett,2008,18(4):1293-1296.
[10]唐玉焕,林克江,尤启冬.基于2D分子指纹的分子相似性方法在虚拟筛选中的应用[J].中国药科大学学报,2009,40(2):178-184.
[11]Ulhaq Z,Saeed M,Halim SA,et al.3D structure prediction of humanβ1-adrenergic receptor via threading-based homology modeling for implications in structure-based drug designing[J].Plos One,2015,10(4):1-19.
[12]Ren J,Esnouf R,Garman E,et al.High resolution structures of HIV-1 RT from four RT-inhibitor complexes[J].Nat Struct Biol,1995,2(4):293-302.
[13]Hopkins AL,Ren J,Tanaka H,et al.Design of MKC-442(emivirine)analogues with improved activity against drugresistant HIV mutants[J].J Med Chem,1999,42(22):4500-4505.
[14]Hopkins AL,Ren J,Esnouf RM,et al.Complexes of HIV-1reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors[J].J Med Chem,1996,39(8):1589-1600.
[15]Ren J,Nichols CE,Chamberlain PP,et al.Crystal structures of HIV-1 reverse transcriptases mutated at codons 100,106and 108 and mechanisms of resistance to non-nucleoside inhibitors[J].J Mol Biol,2004,336(3):569-578.
[16]Hare S,Gupta SS,Valkov E,et al.Retroviral intasome assembly and inhibition of DNA strand transfer[J].Nature,2010,464(7286):232-236.
[17]Valkov E,Gupta SS,Hare S,et al.Functional and structural characterization of the integrase from the prototype foamy virus[J].Nucleic Acids Res,2009,37(1):243-255.
[18]Hu JP,He HQ,Tang DY,et al.Study on the interaction between diketo-acid inhibitors and prototype foamy virus integraseDNA complex via molecular docking and comparative molecular dynamics simulation methods[J].J Biomol Strut Dyn,2013,31(7):734-747.
[19]Hare S,Vos AM,Clayton RF,et al.Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance[J].PNAS,2010,107(46):20057-20062.
[20]Hare S,Smith SJ,Métifiot M,et al.Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir(S/GSK1349572)[J].Mol Pharm,2011,80(4):565-572.
[21]Stanton RA,Nettles JH,Schinazi RF.Ligand similarity guided receptor selection enhances docking accuracy and recall for non-nucleoside HIV reverse transcriptase inhibitors[J].JMol Model,2015,21(11):1-9.
[22]王琴,梅虎,孙家英,等.二芳基三嗪类HIV-1逆转录酶抑制剂的分子对接及3D-QSAR研究[J].化学通报,2011,74(1):54-60.
[23]郑杰,赵斌,闫鸿鹏,等.雪卡毒素毒性机理的分子对接及分子动力学研究[J].化学学报,2011,69(11):2026-2030.
[24]胡衍保,彭静波,顾硕,等.复方心可舒治疗冠心病多靶点作用的分子对接[J].物理化学学报,2012,28(5):1257-1264.
[25]Jasuja H,Chadha N,Kaur M,et al.Dual inhibitors of Janus kinase 2 and 3(JAK2/3):designing by pharmacophore-and docking-based virtual screening approach[J].Mol Divers,2014,18(2):253-267.
[26]Grawenhoff J,Engelman AN.Retroviral integrase protein and intasome nucleoprotein complex structures[J].World JBiol Chem,2017,8(1):32-44.
[27]Chen W,Zhan P,Wu JD,et al.The development of HEPTtype HIV non-nucleoside reverse transcriptase inhibitors and its implications for DABO family[J].Curr Pharm Des,2012,18(27):4165-4186.
[28]Zhang L,Tang XW,Cao YY,et al.Synthesis and biological evaluation of novel 2-arylalkylthio-5-iodine-6-substitutedbenzylpyrimidine-4(3H)-ones as potent HIV-1 non-nucleoside reverse transcriptase inhibitors[J].Molecules,2014,19(6):7104-7121.
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