Modeling the Antiviral Activity of Polyphenols against Variola: Exploration of Inhibitory Candidates for TMPK and TMPK Enzymes.

Background: The aim of this study is to use modeling methods to estimate the antiviral activity of natural molecules extracted from for the treatment of variola which is a zoonotic disease posing a growing threat to human survival. The recent spread of variola in nonendemic countries and the possibility of its use as a bioterrorism weapon have made it a global threat once again. Therefore, the search for new antiviral therapies with reduced side effects is necessary.

Methods: In this study, we examined the interactions between polyphenolic compounds from , a plant known for its antiviral activity, and two enzymes involved in variola treatment, VarTMPK and HssTMPK, using molecular docking.

Results: The obtained docking scores showed that among the 152 selected polyphenolic compounds; many ligands had high inhibitory potential according to the energy affinity. By considering Lipinski's rules, we found that Liquiritin and Olivil molecules are the best candidates to be developed into drugs that inhibit VarTMPK because of their high obtained scores compared to reference ligands, and zero violations of Lipinski's rules. We also found that ginkgolic acids have good affinities with HssTMPK and acceptable physicochemical properties to be developed into drugs administered orally.

Conclusion: Based on the obtained scores and Lipinski's rules, Liquiritin, Olivil, and ginkgolic acids molecules showed interesting results for both studied enzymes, indicating the existence of promising and moderate activity of these polyphenols for the treatment of variola and for possible multi-targeting. Liquiritin has been shown to exhibit anti-inflammatory effects on various inflammation- related diseases such as skin injury, hepatic inflammatory injury, and rheumatoid arthritis. Olivil has been shown to have antioxidant activity. Olivil derivatives have also been studied for their potential use as anticancer agents. Ginkgolic acids have been shown to have antimicrobial and antifungal properties. However, ginkgolic acids are also known to cause allergic reactions in some people. Therefore, future studies should consider these results and explore the potential of these compounds as antiviral agents. Further experimental studies and are required to validate and scale up these findings.