Structure-based Design, Synthesis, Evaluation Of Novel HIV-1 Gp120 Inhibitors And QSAR Studies Of NNRTIs

AIDS is an infectious disease that seriously threatens human health.The main pathogen of AIDS is Human Immunodeficiency Virus Type 1(HIV-1).Highly Active Antiretroviral Therapy(HAART)is currently the most effective method for the treatment of AIDS.However,due to the high mutation rate and gene recombination rate,the rapid emergence of drug resistance greatly reduces the clinical efficacy of HAART.Therefore,the discovery of novel targets and development of highly effective inhibitors with novel mechanisms are urgent needs for the treatment of AIDS.Part I:Design,synthesis,and activity evaluation of phenyloxalamide HIV-1 gp 120 inhibitors.The binding of gp120 to CD4 is the first step of HIV-1 entry into cells.Theoretically,interfering with this process can prevent HIV from recognizing target cells and inhibit viral replication.With high-throughput screening method,NBD-556 was identified a gp 120 inhibitor,which can inhibit viral entry by inhibiting gp120-CD4 interaction.However,the activity of NBD-556 needs to be further improved.The NBD-556/gp120 complex showed that NBD-556 interacted with Phe43 cavity of gp120 protein,but had no interactions with the key Asp368 residue at the gp120-CD4 interaction interface,resulting in its weaker binding ability to gp120.In this chapter,with NBD-556 as the lead compound,a multi-site binding drug design strategy was used to design novel inhibitors targeting the "Phe43 cavity" and the key residue Asp368 simultaneously.The structures of all compounds were confirmed by mass spectrometry,1H NMR and 13C NMR.The antiviral activity of this series of compounds was tested in vitro by luciferase assay(SupTl cells/HIV-1 pNL4.3).The results showed that compounds LL-2,LL-12,LL-14,and LL-18 showed micromolar antiviral activity.LL-2(EC50=1.897 μM)was proved to be the most potent inhibitor,and its activity is about 2-fold potent than that of the lead NBD-556(EC50=3.611 μM).SPR results showed that LL-2,LL-12,LL-14 and LL-18 had higher affinity with gp120 protein than tat of NBD-556,indicating that the target of these comppunds was HIV-1 gp120.Docking simulation demonstrated that compound LL-2 could stretch into Phe43 cavity and form hydrogen bonds with Asp368 residues,which was consistent with our design strategy.In conclusion,based on the interaction of gp120 with CD4,this study enriched the structure activity relationship of phenyl oxalamide inhibitors,and laid a foundation for the discovery of novel HIV-1 gp120 inhibitors with high activity and low toxicity.Part II:Quantitative structure-activity relationship study of HIV-1 reverse transcriptase inhibitorsQuantitative structure-activity relationship(QSAR)is a quantitative study of the relationship between the structural properties of compounds and the target effects,which can guide the structural modification of compounds utilizing the physical and chemical properties or structural parameters of molecules.HIV-1 Reverse Transcriptase Inhibitors(RT)can inhibit the reverse transcription of single-stranded RNA to double-stranded DNA,which plays an important role in the HIV-1 life cycle.Among them,Non-nucleoside Reverse Transcriptase Inhibitors(NNRTIs)have the advantages of high efficiency and low toxicity,being an important part of HAART.Diarylpyrimidines(DAPYs)and Diarylnicotinamides(DANAs)are two types of NNRTIs that have been widely studied.In this chapter,a total of 42 DAPY and DANA derivatives were studied by two-dimensional and three-dimensional quantitative structure-activity relationships.By constructing two-dimensional and three-dimensional QSAR models based on compound structures,the structure optimization directions of the two classes of compounds were explored,which provided a basis for the design of HIV-1 NNRTIs with improved drug resistance profiles.