NON-ACTIVE SITE BINDERS MIGHT RESTORE BACK ANTI-RETROVIRAL DRUGS ACTIVITY IN RESISTANT FORM OF HIV PROTEASE

LUCHI, ADRIANO MARTIN; ANGELINA, EMILIO LUIS; OLSON, ARTHUR; GOROSTEGUI, RENZO NAHUEL; VISCONTI, DANA ; FORLI, STEFANO; BOGADO, MARIA LUCRECIA; PERUCHENA, NÉLIDA MARIA

Montevideo

Congreso; XLII Congreso de Químicos Teóricos de Expresión Latina (QUITEL); 2016

Universidad de la República

p { margin-bottom: 0.1in; line-height: 120%; }Nowadaysthere are several HIV-1 protease (HIV-PR) inhibitors approved.Nevertheless, mutations in HIV-PR can make some parts of it moreflexible and thus destabilize and release the inhibitor. [1]Inthis work we have performed long Molecular Dynamics (MD) simulationsof wild type (WT) and 6X variant of HIV-PR bound to TL-3. Thesimulations show that on going from WT to 6X the equilibrium shiftfrom closed to semi-open conformation of the flaps. Then weattached an small fragment Br6 to the flap of 6X and performed MDsimulations of the ternary complex 6X/TL-3/Br6 (see Fig1). To oursurprise, Br6 was able to restore back the enzyme to closedconformation of theflaps,that is to say it behaves much like the WT form of HIV-PR. Thisfinding supports the hypothesis already proposed by Olson´s groupthat allosteric inhibitors, in combination with active siteinhibitors would likely increase the number of HIV-PR mutationsrequired for significant clinical resistance to the highly activeanti-retroviral therapy (HAART) ´cock- tails´[2].References[1]Y. Yu, J. Wang, Q. Shao, J. Shi, W. Zhu, ?Effects of drug-resistantmutations on the dynamic properties of HIV-1 protease and inhibitionby Amprenavir and Darunavir? 5 (2015) 10517.[2]A.L. Perryman, Q. Zhang, H.H. Soutter, R. Rosenfeld, D.E. McRee, A.J. Olson, J.E. Elder, D. Stout, ?Fragments-Based screen against HIVprotease? Chem. Biol. Drug Des., 75 (2010) 257-268.