A computational study for rational HIV-1 non-nucleoside Reverse Transcriptase inhibitor selection and the discovery of novel allosteric pockets for inhibitor design

HIV drug resistant mutations that render the current Highly Active Anti-Retroviral Therapy cocktail drugs ineffective are increasingly reported. To study the mechanisms of these mutations in conferring drug resistance, we computationally analyzed fourteen Reverse Transcriptase (RT) structures of HIV-1 on the following parameters: drug-binding pocket volume, allosteric effects caused by the mutations, and structural thermal stability. We constructed structural correlation-based networks of the mutant RT-drug complexes and the analyses support the use of Efavirenz as the first-line drug, given that cross-resistance is least likely to develop from Efavirenz-resistant mutations. On the other hand, Rilpivirine-resistant mutations showed the highest cross-resistance to the other non-nucleoside reverse transcriptase inhibitors. With significant drug cross-resistance associated with the known allosteric drug-binding site, there is a need to identify new allosteric druggable sites in the structure of reverse transcriptase. Through computational analyses, we found such a novel druggable pocket on the HIV-1 RT structure that is comparable with the original allosteric drug site, opening the possibility to the design of new inhibitors.

Journal Paper
Bioscience Reports, 5 Feb 2018, doi: 10.1042/BSR20171113
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