Olayide A. Arodola
University of KwaZulu-Natal
South Africa
Title: Could the FDA-approved anti-HIV drugs be promising anti-cancer agents? Answer from extensive molecular dynamics analyses
Biography
Biography: Olayide A. Arodola
Abstract
Based on experimental data, the anticancer activity of nelfinavir, an FDA-approved HIV-1 protease inhibitor, was reported. Nevertheless, the mechanism of action of NFV is yet to be verified. It was hypothesized that the anticancer activity of nelfinavir is due to its inhibitory effect on Heat Shock Protein 90 (Hsp90), a promising target for anticancer therapy. Such findings prompted us to investigate the potential anti-cancer activity of all other FDA-approved HIV-1 protease inhibitors against human Hsp90. To accomplish this, “loop docking” – an enhanced developed in-house molecular docking approach –followed by molecular dynamic simulations and post-dynamic analyses were performed to elaborate on the binding mechanism and relative binding affinities of nine FDA-approved HIV-1 protease inhibitors against human Hsp90. Due to the lack of the X-ray crystal structure of human Hsp90, homology modelling was performed to create its 3D structure for subsequent simulations. Results showed that nelfinavir has better binding affinity (∆G = -9.2 kcal/mol) when compared to other protease inhibitors – this is in a reasonable accordance with the experimental data (IC50 3.1µM). Indinavir, saquinavir and ritonavir have close binding affinity to nelfinavir (∆G = -9.0, -8.6 and -8.5 kcal/mol, respectively). Per-residue interaction energy decomposition analysis showed that hydrophobic interaction (most importantly with Val534 and Met602) played the most predominant role in drug binding. To further validate the docking outcome, 5ns MD simulations were performed in order to assess the stability of the docked complexes. To our knowledge, this is the first account of detailed computational investigations aimed to investigate the potential anticancer activity and the binding mechanism of the FDA-approved HIV PIs binding to human Hsp90. Information gained from this study should also provide a route map towards the design, optimisation and further experimental investigation of potential derivatives of PIs to treat HER2+ breast cancer