Drug Resistance Mechanism of L10F, L10F/N88S and L9OM mutations in CRFOl_AE HIV-1 protease: Molecular dynamics simulations and binding free energy calculations

HIV-1 protease plays a crucial role in viral replication and maturation, which makes it one of the most attractive targets for anti-retroviral therapy. The majority of HIV infections in developing countries are due to non-B subtype. Subtype AE is spreading rapidly and infecting huge population worldwide. The mutations in the active site of subtype AE directly impair the interactions with the inhibitor. The non active site mutations influence the binding of the inhibitor indirectly and their resistance mechanism is not well understood. It is important to design new effective inhibitors that combat drug resistance in subtype AE protease. In this work, we examined the effect of non active site mutations LIOF, Ll OF/N88S and L9OM with nelfinavir using molecular dynamics simulation and binding free energy calculations. The simulations suggested that the LIOF and LI OF/N88S mutants decrease the binding affinity of nelfinavir, whereas the L9OM mutant increases the binding affinity. The formation of hydrogen bonds between nelfinavir and Asp30 is crucial for effective binding. The benzamide moiety of nelfinavir shows large positional deviation in LI OF and L10F/N88S complexes and the LIOF/N88S mutation changes the hydrogen bond between the side chain atoms of 30th residue and the 88th residue. Consequently the hydrogen bond interaction between Asp30 and nelfinavir are destroyed leading to drug resistance. Our present study shed light on the resistance mechanism of the strongly linked mutation L10F/N88S observed experimentally in AE subtype. (C) 2017 Elsevier Inc. All rights reserved.