Uso de técnicas ab initio no estudo de interações entre dois potenciais compostos farmacológicos e a protease da cepa mutante do vírus HIV-1

Abstract

The inhibition of HIV-1 protease is a cornerstone of antiretroviral therapy. However, the notorious ability of HIV-1 to develop resistance against protease inhibitors (PIs) presents a significant challenge by turning currently available therapeutic options ineffective. Among the protease inhibitors available on the market, Darunavir (DRV) is one of the primary treatment options for patients with infections caused by mutant variants of HIV. However, the emergence of strains resistant to Darunavir is particularly dangerous, as it reduces the efficacy of this essential drug, limits the available therapeutic options, and increases the risk of treatment failure. From this perspective, this study aims to represent the interactions between two new PIs, GRL-004 and GRL-063, with the protease (PR) of a mutant (MUT) variant of HIV-1, using docking tools and molecular dynamics (MD) simulations to obtain the ideal conformations between both drugs and the mutant PR of the virus. Our simulations utilized crystals obtained from the Protein Data Bank (PDB). After selecting the corresponding structures of GRL-004, GRL-063, and mutant PR with acquired resistance to DRV, a series of optimizations were performed on the protein to identify its ideal binding conformations, forming the appropriate protein-ligand complex. These conformations were subjected to MD simulations to select the lowest energy state and the most stable conformation among all the obtained replicas. With the ideal replica in hand, one of these complexes (PRMUT-GRL-063) was subjected to quantum calculations to determine its interaction energies. Notably, no repulsion was identified in the interactions between the GRL-063 ligand and the mutant HIV protease. Amino acids VAL50A* and VAL50B* demonstrated good energetic results given their functional importance in the protease, reinforcing the ligand's efficacy. Other amino acids highlighted by the presented energies were PRO81B, ARG8A, PHE82A*, and ASN25A*. This study enhances our understanding of receptor-ligand dynamics and the adaptability of new protease inhibitors, carrying profound implications for the innovation of future antiretroviral medications.