The Research Of Anti-HIV-1Pharmacodynamics And Mechanism On Chroman Compounds

Human immunodeficiency virus (HIV) can cause human lethal disease AIDS(Acquired Immunodeficiency Syndrome, AIDS). The HIV-1is the main prevalentsubtype virus, and exists multiple drug targets and potential targets in the replicationcycle. Integrase is one of the three basic enzymes of viral replication required, capableof catalyzing the virus which integrate their own genes into the gene sequence of hostcell. According to UNAIDS, the global number of AIDS patients reached about30millions. Drugs against the HIV-1treatment exists serious resistanceproblem,therefore it is urgent to develop safe drug effective against new targets.In this study, we used BIAcore SPR to screen several classes of compoundsagainst to the integarse and the reverse transcriptase of HIV-1. Then we selectedKA104which was very effective in screenings and its similar compound KA103toresearch their pharmacodynamics via MAGI test. In addition we explored their targetsand mechanism, combined with computer simulation of drug effects andpharmacokinetic properties. The result showed, KA103and KA104have goodantiviral activity, IC50was4.86μg/ml (17.48μM) and1.03μg/ml (17.82μM),treatment indices were19.88and40.87. The research on the drug targets andmechanisms demonstrated KA103and KA104can not be used on Vif targets. KA104has a stronger binding ability of integrase, dosing could significantly inhibit the virusquantity in viral integration time. The synergy ability research of KA103and KA104found that they affect each other in a relationship of additive effect with potential ofcombination. Through the analysis of docking method of computer to the effect ofKA104on the integrase, the effect has a lot in common compared with the positivecontrol drug. In addition, by ADMET pharmacokinetics software for drug analysis, weforecasted the indexes of clinical experiment, to provide the data foundation for thefurther research and development.