Discovery of HIV-1 integrase Inhibitors: Pharmacophore Mapping, Virtual Screening, Molecular Docking, Synthesis and Biological Evaluation

Abstract

HIV-1 integrase enzyme plays an important role in life cycle of HIV and responsible for integration of virus into human genome. Here, both computational and synthetic approaches were used to design and synthesize newer HIV-1 integrase inhibitors. Pharmacophore mapping was performed on 20 chemically diverse molecules using DISCOtech and refinement was carried out using GASP. Ten pharmacophore models were generated and model 2, containing 4 features including 2 donor sites, 1 acceptor atom and 1 hydrophobic region, was considered the best model as it has highest fitness score. It was used as a query in NCI and Maybridge databases. Molecules having more than 99% Qfit value were used to design 30 molecules bearing pteridin ring and were docked on co-crystal structure of HIV-1 integrase enzyme. Among these, 6 molecules, showing good docking score compared to the reference standards, were synthesized by conventional as well as microwave assisted methods. All compounds were characterized by physical and spectral data and evaluated for in vitro anti-HIV activity against the replication of HIV-1 (IIIB) in MT-4 cells. The used approach of molecular docking and anti-HIV activity data of designed molecules will provide significant insights to discover novel HIV-1 Integrase Inhibitors.