Exploring the Anti-Sars-Cov-2 Potential of Passiflora Flavonoids: An In-Silico Investigation of Main Protease (Mpro) Inhibition

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global health concern for which broadly effective oral antivirals are still limited. The viral main protease (Mpro, also called 3CLpro) is an essential, highly conserved enzyme that mediates the maturation of viral polyproteins, making it one of the most attractive druggable targets. In this study we used molecular docking to investigate the inhibitory potential of ten flavonoids characteristic of the genus Passiflora — the C-glycosyl flavones isoorientin, isovitexin, vitexin and orientin, the O-glycosides hyperoside and astragalin, and the aglycones quercetin, luteolin, kaempferol and chrysin against the crystal structure of SARS-CoV-2 Mpro (PDB ID: 6LU7). The co-crystallised peptidomimetic inhibitor N3 (S = -9.7822 kcal/mol) and the repurposed drug chloroquine (S = -5.1753 kcal/mol) were used as references. All ten Passiflora compounds outperformed chloroquine. Hyperoside (-8.3874 kcal/mol) and astragalin (-8.2122 kcal/mol) showed the most favourable scores, followed by the C-glycosyl flavones isoorientin, vitexin, orientin and isovitexin (-7.4 to -7.9 kcal/mol). The top ligands engaged key substrate-binding residues of the active site, including the catalytic His41, the oxyanion-hole region around Asn142/Gly143/Cys145, and the anchoring residues Glu166, Gln189 and Thr190. ADME/drug-likeness analysis (SwissADME) indicated that aglycones such as quercetin, luteolin, kaempferol and chrysin fully satisfy Lipinski's rule of five, whereas the more potent glycosides violate one to two criteria owing to their high polarity. These computational results support the traditional and nutritional interest of Passiflora and identify its flavonoids  particularly the glycosylated derivatives  as promising natural scaffolds for the design of Mpro inhibitors, warranting further in-vitro and in-vivo validation.