2-D QSAR Studies On Diarypyrimidines As Inhibitors Of HIV-1Reverse Transcriptase Wild And Mutant Type

As an important drug target against HIV-1virus, Reverse Transcriptase(RT) plays avital role in lifecycle of HIV-1virus by transcribing virus’ RNA to double DNA whichrelies on activity of polymerase and ribonuclease. Nonnucleoside reverse transcriptaseinhibitors(NNRTIs) have different structures and mechanism in comparasion withnucleoside reverse transcriptase inhibitors(NRTIs). For advantages of structuraldiversities, high effectivity, low toxicity and cooperation with other drugs duringapplied in therapy, studying of NNRTIs is an effective,important way to find newdrugs in anti-HIV virus. As one new type of NNRTIs, DAPYs (Diarylprimidines)have high activity and low toxicity in inhibiting mutant HIV-1virus. For exploringmechanism of DAPY-RT and selecting high specificity,low toxicity and goodtolerance of drug resistance of new HIV-1drugs, QSAR(quantitative structure-activityrelationship)study as a powerful tool in optimizing,modifying molecular was used ininhibiting HIV-1wild type and mutant types. In this paper, series of2D-QSAR studiesin inhibiting HIV-1wild type and mutants Y181C,L100I,Y188L were achieved. Basedon QSAR models, acting mechanism occurred in DAPY-RT was discussed, a newacting model was present and showed the direction of modifying in DAPYs’structures.This work show mainly contents as follows:(1) Calculating and optimizing molecular structures based on the choosed differentquantum chemistry theory levelsStructures of DAPYs were optimized by three quantum chemistry levels (methods)which are RM1,HF,DFT. By choosing different bases, the four optimized geometricmodels were established and the four accuracy classes of results were generated.Extracted useful and effective quantum parameters from geometric models, QSARmodels were established, which showed the linear or nonlinear relationships betweenquantum parameters and inhibiting activities. Many useful information about molecular acting mechanism resulted from QSAR models by comparing anddiscussing.(2) Selection of parameters and establishment of QSAR modelsConcentrated on revealing drug mechanism, topological parameters which arealways used in QSAR study but show none clearly physical chemistry meaning werediscarded. Quantum chemistry parameters which were objective, accurate, vivid havespecifical meaning in explaining mechanism, so they were mainly chosed. In paper,quantum chemistry parameters combining with geometric parameters, physicalchemical parameters, indicated parameters were used to build QSAR models fordiarylpyrimidines against HIV-1reverse transcriptase. MLR methods were applied inbuilding QSAR models.The selection of parameters for establishing equations and theprocession of building QSAR models followed strictly in rules of mathematicalstatistics. Then finally all the stable and reliable models were checked and testified bysignificant analyzing.(3) Clarifying acting mechanism based on the achieved QSAR models and givingopinions on modified structures of DAPYs.In comparison with different accuracy classes of parameters resulting from QSARmodels, analyzing the significance of important parameters in different virus types ofQSAR models and combining the reported articles about acting mechanism of DAPY-RT, a new possible acting model was proposed. By modifying structures andsimulating optimized molecules, several new molecular geometries were chose viacomparing the important parameter M8Nin different types.Those new molecules showhigh potential inhibiting activity, but more further experiments need to be tested.