In silico evaluation of H1-antihistamine drugs as potential inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase: A repurposing study for COVID-19 therapy

INTRODUCTION: SARS-CoV-2, from the Coronaviridae family, is the seventh known type of coronavirus to infect humans and causes acute respiratory syndrome. Rapidly spreading worldwide, the virus emerged in Wuhan, China, in December 2019, leading to an ongoing pandemic with over 775 million confirmed cases and more than 7 million deaths (as of May 5th 2024), according to World Health Organization data. Although vaccination efforts have been undertaken, the lack of an FDA-approved antiviral agent aimed at curing the disease has made the drug repurposing approach an important strategy for urgent intervention in the COVID-19 pandemic. This study investigates the potential of H1-antihistamines as antiviral agents against SARS-CoV-2, the virus responsible for COVID-19. We targeted the main replicase/transcriptase complex (RTC) of the virus, specifically nonstructural protein 12 (nsp12), which is essential for viral RNA synthesis.
METHODS: Using molecular docking techniques, we explored the interactions between H1-antihistamines and RNA-dependent RNA polymerase (RdRp), a key enzyme in viral replication. The three-dimensional structure of 37 H1-antihistamine molecules was drawn and their energies were minimized using Spartan 0.4. Subsequently, we conducted a docking study with Autodock Vina to assess the binding affinity of these molecules to the target site. The docking scores and conformations were then visualized using Discovery Studio.
RESULTS: The results examined showed that the docking scores of the H1-antihistamines were between -5.0 and -8.3 kcal/mol. The findings suggest that among all analyzed drugs, bilastine, fexofenadine, montelukast, zafirlukast, mizolastine, rupatadine can bind with the best binding energy (< -7.0 kcal/mol) and inhibit RdRp, potentially halting the replication of the virus.
DISCUSSION AND CONCLUSION: This study highlights the promise of H1-antihistamines in combating COVID-19 and underscores the value of computational approaches in rapid drug discovery and repurposing efforts. Finally, experimental studies are required to measure the potency of H1-antihistamines before their clinical use against COVID-19 as RdRp inhibitors.