Non-active site binders might restore back anti-retroviral drugs activity in resistant form of HIV protease

LUCHI, ADRIANO M.; VISCONTI, D. M.; GOROSTEGUI, R. N.; BOGADO, M. L. ; ANGELINA, EMILIO; FORLI, S.; OLSON, A. G. ; PERUCHENA, N. M.

Montevideo

Congreso; QUITEL 2016, 42nd International Congress of Theoretical Chemists of Latin Expression Montevideo, Uruguay, November 20th-25th 2016; 2016

QUITEL

Nowadays there are several HIV-1 protease (HIV-PR) inhibitors approved. Nevertheless, mutations in HIV-PR can make some parts of it more flexible and thus destabilize and release the inhibitor. [1]In this work we have performed long Molecular Dynamics (MD) simulations of wild type (WT) and 6X variant of HIV-PR bound to TL-3. The simulations show that on going from WT to 6X the equilibrium shift from closed to semi-open conformation of the flaps. Then we attached an small fragment Br6 to the flap of 6X and performed MD simulations of the ternary complex 6X/TL-3/Br6 (see Fig1). To our surprise, Br6 was able to restore back the enzyme to closed conformation of the flaps, that is to say it behaves much like the WT form of HIV-PR. This finding supports the hypothesis already proposed by Olson´s group that allosteric inhibitors, in combination with active site inhibitors would likely increase the number of HIV-PR mutations required for significant clinical resistance to the highly active anti-retroviral therapy (HAART) ´cock- tails´[2].