A Search for New Inhibitors of HIV-1 Integrase Using Methods of Structural Bioinformatics

Human immunodeficiency virus (HIV) is a causative agent of HIV-infection which is a deadly dangerous and common disease, with HIV-1 being the most common subtype. Billions of U.S. dollars are spent on HIV control, treatment and prevention all over the world every year. Specific characteristics of HIV-1 life cycle is a basis for a quick emergence of drug resistance, which implies a necessity for development of new antiretroviral drugs. HIV-1 integrase inhibitors is one of the promising but under-represented in clinical practice classes of drugs. One of the major problems in the development of new HIV-1 integrase inhibitors is a lack of fully experimentally resolved structure of HIV-1 integrase. This work is dedicated to a search of new potential HIV-1 integrase inhibitors. In this study a model of HIV-1 intasome – a protein complex formed by several integrases – was designed using a homology modeling on the basis of spatial structures of Rous sarcoma virus, human foamy virus and mouse mammary tumor virus intasomes extracted from Protein Data Bank. The pharmacophore model was designed based on three known HIV-1 integrase inhibitors – dolutegravir, raltegravir and elvitegravir. The screening of ZINC database was performed using designed pharmacophore model. The compounds, that were selected and then filtered during virtual screening, were docked into the modeled structure of HIV-1 intasome. Finally, 13 compounds were selected, which in our opinion can have inhibitory activity towards HIV-1 integrase.