COMPUTATIONAL CHARACTERIZATION OF NON-ACTIVE SITE MUTATION V77I IN HIV-1 PROTEASE: POSSIBLE CONTRIBUTION TO NELFINAVIR RESISTANCE AND DEVELOPMENT OF NEW DRUG LEADS TARGETING HIV-1 PROTEASE

Abstract

BACKGROUND The Human immunodeficiency virus (HIV-1) protease is an attractive target for antiviral treatment and a number of therapeutically useful inhibitors have been designed against it. The emergence of drug resistant mutants of HIV-1 pose a serious problem for the conventional therapies been used so far. Here we have tried to study the effect of V77I mutation along with the co-occurring mutations L33F and K20T through multinanosecond molecular dynamics simulations. V77I is known to cause Nelfinavir (NFV) resistance in subtype B population of HIV-1 protease. We have reported the effect of this clinically relevant mutation on the binding of NFV and the conformational flexibility of the protease, and tried to generate derivates of potent drug Nelfinavir which can efficiently inhibit the wild and mutant proteases. RESULT The study proposes that V77I-L33F mutant (DBM) showed greater flexibility and the flap separation was more with respect to the wild protease. The cavity size of stabilized DBM was also found to be increased which is responsible for the decreased interaction of Nelfinavir with all the cavity residues and hence decreased its binding affinity (Glide XP score: wild= -9.3, DBM= -7.8). On the other hand the binding affinity of V77I-L33F-K20T mutant (TPM) was found to be increased for Nelfinavir (Glide XP score= -10.3). The flap separation of TPM was less and the cavity size had also reduced with respect to wild protease. CONCLUSION The resistant mutations had made DBM more stable in environment whereas the addition of third mutation K20T had made the protease TPM more susceptible to Nelfinavir. This lowered resistance can be the reason behind the less clinical relevance of TPM.