Phytochemicals from Terminalia brownii and Acacia asak as natural inhibitors of SARS-CoV-2 main protease: In Vitro, molecular docking, and simulation analysis

The continuous emergence of SARS-CoV-2 variants and the absence of a definitive cure underscore the need for effective antiviral agents. In this study, the alcoholic extracts of Terminalia brownii and Acacia asak —among 18 Saudi medicinal plants screened—showed the highest inhibitory activity against the SARS-CoV-2 main protease (Mpro) [ 1 ], with inhibition rates of 95.3% and 95.2%, respectively, at 100 μg/mL. A bioassay-guided fractionation of the active n-butanol extract from T. brownii yielded eleven compounds, including phenolic acids, hydrolysable tannins, and one flavonoid. Additionally, four flavonoids were isolated from A. asak . Structural elucidation of all compounds was performed using spectroscopic methods and literature comparison. Molecular docking studies using AutoDock 4.2 identified compounds 4, 5, 10 (from T. brownii ), and 14 (from A. asak ) ([ Fig. 1 ]) as promising Mpro inhibitors, with binding energies of –9.3, –8.5, –8.1, and –7.8 kcal/mol, respectively. These interactions were further validated through 100 ns molecular dynamics simulations, assessing RMSD, RMSF, Rg, and SASA values. In vitro assays confirmed the inhibitory activity of the four compounds against Mpro, with compound 4 showing the most potent activity (IC 50 =1.2 μg/mL). MM-GBSA binding free energy calculations supported these findings, highlighting compound 4 as the strongest binder. Importantly, none of the tested compounds exhibited significant cytotoxicity against A549 and HUVEC cell lines, suggesting favorable safety profiles. Fig. 1 Chemical structures of the isolated active compounds. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany