Discovery of HIV-I Integrase Inhibitors: Pharmacophore Modeling, Virtual Screening, Synthesis, 3d-qsar Study and in Silico Pharmacokinetic, Toxicity and Bioactivity Prediction

Abstract

HIV I integrase is one of the most important enzyme which play an important role in life cycle of HIV virus. It is responsible for integration of virus into human genome. In course of my research to discover new HIV I integrase inhibitors, both computational and synthetic approaches were used to design and synthesis of newer HIV I integrase inhibitors. Pharmacophore mapping was performed on 20 chemically diverse molecules using DISCOtech and refinement of the same was done using genetic algorithm similarity programme (GASP). Ten pharmacophore models were generated and model 1 was considered the best model as it has highest fitness score compared to all other models. The best pharmacophore hypothesis contained 4 features including 2 donor sites, 1 acceptor atom and 1 hydrophobic region. Model 1 was used as a query in NCI and Maybridge hit finder databases. A total number of 17930 molecules were obtained from 39170 molecules after virtual screening. Molecules having more than 99% Qfit value were used in designing of 30 molecules which contains pteridine ring as a core structure. These 30molecules were docked on HIV I integrase enzyme. Among these 30 molecules, 6 molecules have synthesized which has shown good score compared to the reference standard Raltigravir and Elvitegravir. 3D-QSAR, CoMFA and CoMSIA studies were carried out on Dihydroxypyrimidine carboxamide derivatives in order to predict the activity of synthesized compounds. In silico pharmacokinetic and toxicities studies were also predicted for these 6 molecules. These 6 compounds may act as potent HIV I integrase inhibitors in treatment of acquired immunodeficiency syndrome (AIDS).