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

Abstract

The HIV epidemic has claimed more than 32.7 million live since its emergence in 1981, while many ART and HAART therapies are available and provide relief and control for patients, most of these therapeutics come with long-term side effects, resistance, socio-economical barriers, and other obstacles. In this study, genomic analysis was performed on 98 HIV-1 genomes to determine the most coherent target that could be utilized to restrict and cease the viral replication, the reverse transcriptase enzyme. Following the identification of the target protein, the RNase H activity of the reverse transcriptase was nominated as the potent target given the limited research associated with it. A library of 94 thousand small molecule inhibitors was generated and virtual screening was performed to identify hits, based on the reproducibility of the screening results, 4 compounds with the best scores were considered and their interaction within the active site was analyzed. 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. In silico ADMET assays were performed on the hit compounds to analyze their drug-likeness, physicochemical and pharmacological properties. Phomoarcherin B, a pentacyclic aromatic sesquiterpene naturally found in the endophytic fungusPhomopsis 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.