(192h) Toward Wide-Spectrum Antivirals Against Coronaviruses: Modeling the Binding Mechanisms of Repurposed Drugs to the Sars-Cov-2 RNA-Dependent RNA Polymerase
AIChE Annual Meeting
Monday, November 14, 2022 - 5:15pm to 5:30pm
Effective therapeutic treatments that confer strong attenuation against coronaviruses remain elusive. One of the key protein complexes sharing high sequence similarity between coronaviruses is the RNA-dependent, RNA polymerase (RdRp), a protein complex responsible for mediating replication of the virusâs genome. Previous studies have identified remdesivir a promising repurposed drug against the RdRp of the SARS-CoV-2 virus, with the potential to be regarded as a wide-spectrum coronavirus antiviral thanks to the prevalence of this protein complex among coronaviruses. However, its exact action mechanism, and that of similar nucleotide analogue inhibitors, is not known. In this study, we examine at the molecular level the interaction of this drug and that of similar nucleotide analogue inhibitors, ribavirin and favilavir, by relying on atomistic molecular simulations and advanced sampling. By analyzing the binding free energies of these different drugs, it is found that all of them bind strongly at the active site. Surprisingly, however, ribavirin and favilavir do not bind the nucleotide on the complementary strand as effectively and seem to act by a different mechanism than remdesivir. Remdesivir exhibits similar binding interactions to the natural base adenine. Moreover, by analyzing remdesivir at downstream positions of the RNA, we also find that, consistent with a âdelayedâ termination mechanism, additional nucleotides can be incorporated after remdesivir is added, and its highly polar 1â²-cyano group induces a set of conformational changes that can affect the normal RdRp complex function. By analyzing the fluctuations of residues that are altered by remdesivir binding, and comparing them to those induced by lethal point mutations, we find a possible secondary allosteric mechanism in which remdesivir destabilizes the protein complex and its interactions with the RNA strands. These findings imply that remdesivir or similarly-acting nucleotide inhibitors could potentially be developed as wide-spectrum allosteric antivirals against coronaviruses, which could offer rapid protection against future coronavirus outbreaks.