Abstract
Salvia species are traditionally utilized for treating various health conditions and have shown potential inhibitory effects against SARS-CoV-2. However, their therapeutic potential remains underexplored due to limited research on their chemical composition. Hence, the need to investigate their bioactive compounds and mechanisms of action. This study utilized LC-MS-based metabolomics integrated with molecular networking to profile the chemical constituents of Salvia aurea and Salvia dolomitica and annotate their bioactive compounds. Additionally, molecular docking and network pharmacology approaches were applied to assess the inhibitory potential of these compounds against key SARS-CoV-2 viral proteins and action mechanisms against human target proteins associated with COVID-19. Principal Component Analysis (PCA) revealed distinct groupings and clear separations between the two species, indicating significant variations in their metabolite profiles. A total of 83 compounds were identified, primarily belonging to flavonoids, hydroxycinnamic acids, and terpenes, which are major phytochemical classes in Salvia species. The docking results revealed that compounds diosmin, apigenin-3-glucuronide, hesperidin, and rosamultin demonstrated maximum inhibitory activity against the five important viral proteins (PLpro, Spike protein, Mpro, Helicase, and RdRp) and the network pharmacology revealed a total of eight potentially active compounds and nine core targets that were selected for further analysis. GO and KEGG pathway enrichment analysis revealed potential therapeutic mechanisms against COVID-19 infections through anti-inflammatory effects and could act through the inhibition of the pathway of coronavirus disease-COVID-19. The molecular docking results suggested that all eight active compounds (yunnaneic acid E, salviaflaside, isoacteoside, corosolic acid, cirsiliol, sagerinic acid, aesculetin and peonidin-3-glucoside) can bind to the nine core targets. However, sagerinic acid and corosolic acid were found to be the main active compounds to bind against BTK, EGFR, MAPK10, and TYK2, the main targets for treating COVID-19, with favourable docking scores. This study underscores the effectiveness of LC-MS-based metabolomics in characterizing the phytochemical composition of Salvia species and highlights the role of in silico approaches, such as molecular docking and network pharmacology, in identifying their bioactive compounds and therapeutic mechanisms against COVID-19. The findings provide a basis for further exploration of Salvia species and their potential development into anti-COVID-19 therapeutics.