Emanuela Marchese
| In Silico Approaches to Uncover the Antioxidant and Therapeutic Properties of Polyphenols |
| Marchese Emanuela1, Costa Giosuè1, and Alcaro Stefano1,2 1 Dipartimento di Scienze della Salute, Università“Magna Græcia” di Catanzaro, Campus “S. Venuta”, 88100, Catanzaro, Italy. 2 Associazione CRISEA-Centro di Ricerca e Servizi Avanzati per l’innovazione Rurale, Loc. Condoleo, Belcastro 88055, Italy |
| Abstract Natural products represent a key component in drug discovery, providing structurally diverse bioactive compounds with significant therapeutic potential. An integrated in silico and experimental approach was employed to elucidate both the antioxidant and target-mediated biological properties of polyphenols and their metabolites. Density Functional Theory calculations were used to investigate the radical scavenging mechanisms of gut microbiota-derived metabolites of ellagic acid. Thermodynamic and kinetic analyses identified urolithin D as the most effective compound in neutralizing hydroperoxyl radicals in aqueous environments. Urolithins A and C also demonstrated antioxidant potential, whereas urolithin B showed negligible activity. Experimental assays confirmed that antioxidant activity predominantly proceeds via a single electron transfer (SET) mechanism [1]. The same computational approach was applied to the flavonoid (+)-catechin, highlighting its ability to neutralize free radicals through a hydrogen atom transfer (HAT) mechanism [2]. Beyond the renowned antioxidant properties of polyphenols, the research was turned to investigate target-mediated effects. A virtual screening protocol was able to suggest two best candidates, diosmin and hesperidin, from a subset of FDA-approved polyphenols, as promising proteasome inhibitors. Subsequent biological evaluations confirmed their capacity to inhibit proteasome activity and exert anti-tumor effects in both sensitive and resistant cancer cell lines [3]. Finally, the interaction of urolithins with presynaptic α2-adrenergic receptors was investigated through molecular docking and molecular dynamics simulations. Computational results were fundamental to disclose a huge heterogeneity in the modes by which the three different metabolites interact with the α2 receptor, providing a molecular-level interpretation of the experimental functional data [4]. These findings highlight the value of combining computational and experimental approaches to unravel the mechanisms of natural compounds and support their rational development as therapeutics. |
| References [1] Marchese, E.; Orlandi, V.; Turrini, F.; Romeo, I.; Boggia, R.; Alcaro, S.; Costa, G. In Silico and In Vitro Study of Antioxidant Potential of Urolithins. Antioxidants 2023, 12(3), 697. https://doi.org/10.3390/antiox12030697 [2] Ciardullo, G.; Orlando, C.; Russo, N.; Marchese, E.; Galano, A.; Marino, T.; Prejanò, M. On the dual role of (+)-catechin as primary antioxidant and inhibitor of viral proteases. Computers in Biology and Medicine 2024,180, 108953. doi.org/10.1016/j.compbiomed.2024.108953 [3] Marchese, E.; Gallo Cantafio, M.E.; Ambrosio, F.A.; Torcasio, R.; Valentino, I.; Trapasso, F.; Viglietto, G.; Alcaro, S.; Costa, G.; Amodio, N. New Insights for Polyphenolic Compounds as Naturally Inspired Proteasome Inhibitors. Pharmaceuticals 2023, 16(12), 1712. https://doi.org/10.3390/ph16121712 [4] Torre, V.; Marchese, E.; Willison, E.; Monaco, M.; Bozzo, M.; Atanasio, G.D.N.; … & Pittaluga, A. Presynaptic release-regulating α2 receptors and Urolithins: A bridge between systemic EA administration and central health properties. Biomedicine & Pharmacotherapy 2025, 188, 118187. doi.org/10.1016/j.biopha.2025.118187 |