QSAR And Molecular Docking Studies On Diarylpyrimidine Analogues As HIV-1NNRTIs

Reverse transcriptase (RT) is an essential enzyme in the life cycle of humanimmunodeficiency virus (HIV) and is also an important target for anti-HIV drugs. So far,the existing RTs as targets for anti-HIV drugs are divided into nucleoside reversetranscriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors(NNRTIs). The new HIV-1NNRTI drugs Etravirine (TMC125) and Rilpivirine (TMC278),which were approved by the American FDA in2008and2011, respectively, arecompounds belonging to the diarylpyrimidine (DAPY) family. They are extremely highpotent against both wild type and multiple drug-resistant HIV-1strains. Thus, DAPYs hasbecome one of the hot-spot researches in the field of anti-HIV drugs.In this study, a series of DAPYs were obtained as the research object, using directdrug design method in combination with indirect drug design method. Three dimensional(3D) quantitative structure-activity relationships and molecular docking studies on threedifferent series of DAPYs were performed, and the result was help to provide certaininstructions in developing efficient DAPYs anti-HIV drugs.The main work is as follows:1. Using both the comparative molecular field analysis (CoMFA) and thecomparative molecular similarity analysis (CoMSIA) methods, the relationships betweendimensional structures and anti-HIV-1activities of39naphthyl-substituteddiarylpyrimidines (naph-DAPYs) were studied, also, good CoMFA and CoMSIA modelswith preferable prediction abilities were achieved. Finally, the39naph-DAPYs weredocked into its targets HIV-1RT using the method of molecular docking to analyze theirbinding modes and interactions.2. In combination with3D-QSAR method (CoMFA and CoMSIA) and moleculardocking method, the relationships between structures and activities of36diarylpyrimidineanalogues were studied. Also, the interactions between these36DAPYs and HIV-1RT was explored. Finally, the binding modes and interactions between these DAPYs and HIV-1RTwere discussed in the aspects of steric, electrostatic, hydrophobic, H-bond donor andacceptor fields.3. The relationships between anti-HIV-1activities and structures of41CH2-DAPYs,which were collected from literatures, were explored in this study. And the binding modesand interactions between these CH2-DAPYs and HIV-1RT were studied by usingmolecular docking method4. The common features between these three series of DAPYs were studied.DISCOtech module was used to search common pharmacophore models, and CoMFAresearch was done in following.The pharmacophore model had six active sites, which weretwo aromatic ring centers, two hydrogen bond donor centers and two hydrophobic centers.The pharmacophore model was consistent with experimental results of previous3D-QSAR and molecular docking studies.