Identificación y modelamiento de mutaciones que otorgan resistencia a inhibidores de la enzima ARN polimerasa ARN dependiente del virus SARS-CoV-2

Abstract

The emergence of a new severe acute respiratory syndrome coronavirus (SARS-CoV-2), of which there is not yet effective treatment, so the SARS-CoV-2 dependent RNA polymerase (RdRp) enzyme, is one of the main goals for developing compounds with antiviral activity. Based on this principle, structural analogues of nucleosides such as Favipiravir, Ribavirin and Remdesivir, particularly, the latter is an effective SARS-CoV-2 RdRp inhibitor and other RNA viruses such as MERS being a major candidate as a therapeutic option for the treatment of COVID-19. Key RdRp residues of the virus, which assist in the junction of Remdesivir that maintain non-covalent interactions, were identified. The degree of conservation of these residues was analyzed by multiple sequence alignment with RdRps. This analysis allowed mutant variants to be modeled in three specific positions of the enzyme's active site, Val557Ile, Ala688Gly and Ser759Thr, and evaluate the effect of these mutations on the binding properties of the inhibitor. Affinity and free energy were determined by molecular coupling in the GOLD program. The results show that all three mutations decrease Remdesivir's theoretical affinity for the active RdRp site. The most harmful mutation for the binding of Remdesivir with the enzyme was the Val557Ile variant with an affinity Score 1.4 times lower than that observed for the native enzyme. These results allow us to foresee the effect of possible changes that may occur in the viral polymerase in a natural way and to generate therapeutic alternatives to counteract the effect of resistance to RdRp inhibitors, such as Remdesivir.