COMPUTATIONAL INSIGHTS ON ANTIVIRAL RESISTANCE MECHANISM OF HIV-1 PROTEASE WITH GS-8374

Human immunodeficiency virus type 1 (HIV-1), is an etiologic agent of the most life-threatening disease AIDS. HIV-1 protease (HIVP) is a key enzyme that performs an essential step in the life cycle of the virus. HIV-1 protease assembled as a dimer in the functional form and involved in cutting “polyprotein" into the proper protein-sized pieces. The two chains assemble to form a long tunnel covered by two flexible protein forms a "flaps." The flaps open up, and the enzyme wraps around a protein chain, closing and holding it tightly in the tunnel. Highly active antiretroviral therapy (HAART) is the current successful treatment approach for AIDS and protease inhibitors plays a crucial role in HAART. The drugs that target against protease consider as one of the major approaches in modern medicine. Till date, 26 anti-HIV compounds have been approved by the Food and Drug Administration (FDA), and 10 are HIV protease inhibitors. The antiviral resistance occurs due to a point mutation in the viral protein which has been a big hurdle in the treatment of AIDS. To decipher the resistance mechanism of HIV-1 protease against current drug GS-8374, the computational studies have been carried out. The molecular docking analysis of protease mutants confirms the loss of crucial H-bonds with the drug that in-turn leads to antiviral resistance. In a nutshell, our studies can provide crucial structural insights on the resistance mechanism of HIV-1 protease against GS-8374.