Molecular basis for the repurposing of histamine H2-receptor antagonist to treat COVID-19

Abstract

With the world threatened by a second surge in the number of Coronavirus cases, there is an urgent need for the development of effective treatment for the novel coronavirus (COVID-19). Recently, global attention has turned to preliminary reports on the promising anti-COVID-19 effect of histamine H2-receptor antagonists (H2RAs), most especially Famotidine. Therefore, this study was designed to exploit a possible molecular basis for the efficacy of H2RAs against coronavirus. Molecular docking was performed between four H2RAs, Cimetidine, Famotidine, Nizatidine, Ranitidine, and three non-structural proteins viz. NSP3, NSP7/8 complex, and NSP9. Thereafter, a 100 ns molecular dynamics simulation was carried out with the most outstanding ligands to determine the stability. Thereafter, Famotidine and Cimetidine were subjected to gene target prediction analysis using HitPickV2 and eXpression2Kinases server to determine the possible network of genes associated with their anti-COVID activities. Results obtained from molecular docking showed the superiority of Famotidine and Cimetidine compared to other H2RAs with a higher binding affinity to all selected targets. Molecular dynamic simulation and MMPBSA results revealed that Famotidine as well as Cimetidine bind to non-structural proteins more efficiently with high stability over 100 ns. Results obtained suggest that Famotidine and Cimetidine could be a viable option to treat COVID-19 with a mechanism of action that involves the inhibition of viral replication through the inhibition of non-structural proteins. Therefore, Famotidineand Cimetidine qualify for further study as a potential treatment for COVID-19.

Long covid—mechanisms, risk factors, and management

“…205 Systematic reviews and molecular studies have suggested that histamine-1 and histamine-2 antagonists are viable candidates for further clinical trials in covid-19. [206][207][208] It remains to be seen whether antihistamines have potential for treating long covid. Antidepressants have been proposed to reduce the effects of long covid.…”

Could Histamine H1 Receptor Antagonists Be Used for Treating COVID-19?

“…Similar to H1 receptor antagonists, H2 receptor antagonists could also inhibit various viruses, including HCV and HIV [ 89 ]. Molecular docking results showed that H2 receptor antagonists (cimetidine, famotidine, nizatidine, and ranitidine) could bind to SARS-CoV-2 structural proteins.…”

“…Moreover, the results found that famotidine and cimetidine are more prone to bind the viral proteins compared to nizatidine and ranitidine. Further, kinase enrichment analysis predicted that genes such as ERKs, SMADs, and MAPKs are involved in the antiviral activity of famotidine and cimetidine against SARS-CoV-2 [ 89 ]. In addition to the in-silico modeling, a previous retrospective cohort study has shown that treatment with famotidine was highly associated with reduced risk of mortality [ 90 ].…”

“…However, a recent study revealed that the principal mechanism of action of famotidine for relieving COVID-19 symptoms is attributed to its on-target effect on H2 receptor activity, and is likely independent of other histamine receptors determined by competition assay [ 14 ]. Most recently, molecular docking results suggest that famotidine and cimetidine inhibit SARS-CoV-2 replication through the inhibition of non-structural proteins, including NSP3, NSP7/8 complex, and NSP9 [ 89 ]. The modes of action of anti-SARS-CoV-2 activity of famotidine needs to be further clarified.…”

Fight against Covid-19: Nigella sativa, a Potential Curative

“…Administration of Famotidine (a potent histamine antagonist) has exhibited promising results as all ten patients who participated in a trial, showed a marked reduction in symptoms related to COVID-19 [52]. Correlating with the efficacy of histamine antagonists, it can be safely said that Histamine has an integral role in the pathogenesis of inflammation during the disease [53]. Nigella Sativa seed and its active compounds have been used as a herbal solution that can establish a balanced inflammatory response by suppressing histamine production and promoting a healthy immune response [54].…”