Computational Study of the Resistance Shown by the Subtype B/HIV-1 Protease to Currently Known Inhibitors

Human immunodeficiency virus type 1 protease (HIV-1 PR) is an essential
enzyme in the HIV-1 life cycle. As such, this protein represents a major
drug target in AIDS therapy, but emerging resistance to antiretroviral
inhibitor cocktails, caused by high viral mutation rates, represents a
significant challenge in AIDS treatment. Many mutations are not located
within the active site or binding pocket, nor they do significantly
modify the three-dimensional structural organization of the enzyme;
hence, the mechanism(s) by which they alter inhibitor affinity for the
protease remains uncertain. In this article, we present an all-atom
computational analysis of the dynamic residue-residue coordination
between the active site residues and the rest of the protein and of the
energetic properties of different HIV-1 PR complexes. We analyze both
the wildtype form and mutated forms that induce drug resistance, In
particular, the results show differences between the wild type and the
mutants in their mechanism of dynamic coordination, in the signal
propagation between the active site residues and the rest of the
protein, and in the energy networks responsible for the stabilization of
the bound inhibitor conformation. Finally, we propose a dynamic and
energetic explanation for HIV-1 protease drug resistance, and, through
this model, we identify a possible new site that could be helpful in the
design of a new family of HIV-1 PR allosteric inhibitors.