Phomoarcherin B as a novel HIV-1 Reverse Transcriptase RNase H activity inhibitor; Conclusions from comprehensive computational analysis

Abstract

The HIV-1 and its variants have claimed more than 32.7 million lives since its emergence in 1981, while many highly/ active antiretroviral therapies are available but most of these therapeutics have long-term side effects. In this study, genomic analysis was performed on 98 HIV-1 genomes to determine the most coherent target, which could be utilized for termination of the viral replication and the reverse transcriptase enzyme. Following the identification of the target protein, the RNase H activity of the reverse transcriptase was selected as the potential target based on its low mutation rate and high conservation determined using MAUVE analysis. Afterwards, a library of around 94.000 small molecule inhibitors was investigated and virtual screening was performed against the RNase domain of the reverse transcriptase to identify potential hits. Four compounds with the best scores were considered and their interaction within the active site was analysed. Subsequently, all-atom molecular dynamics simulations and MM-PBSA was performed to validate the stability and binding free energy of the hits within the RNase H active site. In computational analyses, ADMET assays were performed on the hit compounds to analyse their drug candidacy based on their physicochemical and pharmacological properties. Phomoarcherin B, a pentacyclic aromatic sesquiterpene naturally found in the endophytic fungus Phomopsis archeri, known for its anticancer properties scored the best in all the experiments and was nominated as a potential inhibitor of the HIV-1 reverse transcriptase RNase H activity.