Study On The Interaction Between HIV-1 Integrase And Diketo-acid Inhibitors

Acquired immunodeficiency syndrome(AIDS) was first reported in the United States in 1981 and has become a major worldwide epidemic. The latest statistical data of the Joint Nations Program on AIDS shows that an estimated 35.3 million people globally are living with AIDS, and 1.6 million people died from AIDS-related illnesses in 2012. Human immunodeficiency virus type 1(HIV-1), the etiological agent of AIDS, progressively destroys the body?s ability to fight infections and certain cancers, by the means of killing or damaging cells of the body?s immune system. Due to the absence of any known human homolog, HIV-1 integrase(IN), one of the three crucial enzymes which drives the HIV-1 replication process, has gained popularity as a promising target for the discovery of novel anti-HIV drugs. Diketo acids inhibitors(DKAs) are potent and selective IN inhibitors and the interaction mechanism between DKAs and IN is still not understood. Until now, the approved drugs targeted IN are all DKAs, namely raltigravir(RAL), elvitegravir(EVG) and dolutegravir(DTG). However, drug resistance conferred by mutations in the HIV-1 genome, has emerged in a large number of patients. And the efficacy of anti-AIDS drugs is greatly compromised by drug resistance and toxicity. There is in urgent need to develop anti-HIV drugs with considerable toxicity tolerability and an acceptable mutation profile.In this paper, several molecular modeling approaches are used to investigate the interaction of DKAs and IN. The main content of this dissertation includes the following two parts:(1) quantitative structure-activity relationships of DKAsA QSAR(Quantitative Structure-Activity Relationship) analysis was performed to provide insights into the interaction between the chemical structure of DKAs and the inhibition of IN. First, 88 compounds and corresponding activities were obtained from Merck Research Laboratory to form the data set. Based on structure diversity and distribution of IC50, the data was randomly divided into training set and test set. The CoMFA(Comparative Molecular Field Analysis) and CoMSIA(Comparative Molecular Similarity Induces Analysis) models are constructed using partial least squares(PLS) and showed statistically significance(q2 = 0.664, r2 = 0.984 for CoMFA; q2 = 0.642, r2 = 0.976 for CoMSIA) and good predictive(r2pred = 0.780 for CoMFA; r2 pred = 0.741 for CoMSIA). Further interpretation of contour maps provides instructive insights into the optimization and design of lead compounds.(2) Study on the mechanism of DKAs and INThe interaction between IN and two DKAs were investigated using ?relaxed receptor? molecular docking approach and molecular dynamics(MD) simulations. Molecular mechanics Poisson-Boltzmann surface area(MM-PBSA) and molecular mechanics generalized Born surface area(MM-GBSA) were employed to evaluate the binding affinity and the energy decomposition for residues, respectively. Further analysis indicted that the dominating effect of van der Waals interaction drives the binding of IN and DKAs and key residues such as L68, I73, V75, N155, K159, I162 play important roles by forming hydrogen bond, salt bridge and hydrophobic interaction. This conclusion is quite consistent with QSAR model in the relation between structures with inhibitory activity.