Subtle structural differences of nucleotide analogs may affect SARS-CoV-2 RNA-dependent RNA polymerase inhibitory activity

Abstract

The rapid spread and high lethality of the novel SARS-CoV-2 variants that cause COVID-19 continues to produce major global health and social distress. Several vaccines were developed in record time to prevent and limit the spread of the infection, thus playing a pivotal role in controlling the pandemic. Although the repurposing of available drugs attempts to provide therapies of immediate access against COVID-19, there is still a need for developing specific treatments for this disease. Remdesivir remains the only evidence-supported antiviral drug to treat COVID-19 patients, and only in severe cases. To fill this gap, we targeted the viral RNA-dependent RNA polymerase (RdRp) and the exoribonuclease (ExoN) following two strategies. First, we modeled and analyzed nucleoside analogs Sofosbuvir, Remdesivir, Favipiravir, Ribavirin, and Molnupiravir at three key binding sites on the RdRp-ExoN complex. Second, we curated and virtually screened a database containing 517 nucleotide analogs in the same binding sites. Finally, we characterized key interactions and pharmacophoric features presumably involved in viral replication halting at multiple sites. Our results highlight structural modifications that might lead to more potent SARS-CoV-2 inhibitors and provide a collection of nucleotide analogs useful for screening campaigns.