Screening Asian Medicinal Plants for SARS-CoV-2 Inhibitors: A Computational Approach

This work aimed to evaluate the antiviral potential of compounds from Asian medicinal plants against SARS-CoV-2's main protease and spike glycoprotein, identifying dual inhibitors from these plants that target both proteins through advanced virtual screening, molecular dynamics simulations, and pharmacophore analysis. An in-house library of 335 antiviral natural products was prepared from the selected medicinal plants. Following the virtual screening of this library against the main protease and spike glycoprotein, top compounds were subjected to downstream analysis for evaluating druggability potential and toxicity analysis. Molecular dynamic simulations were performed to confirm the stability of interactions between the ligands and target proteins. Our analysis demonstrated 67 compounds as dual inhibitors. The six top dual inhibitors, namely trans-delta-viniferin, trans-E-viniferin, 3,4-DHPEA-EDA, oleuropein aglycone, lactucopicrin, and 11β,13-dihydrolactucopicrin, exhibited superior docking scores and met drug-likeness criteria, including Lipinski's rule, bioavailability, and favorable ADME and toxicity profiles. Trans-delta-viniferin and trans-E-viniferin, featuring a stilbene scaffold, emerged as the most promising candidates due to their stable interactions, minimal fluctuations, and consistent hydrogen bonding across SARS-CoV-2's Mpro and S-protein in MD simulations, while 3,4-DHPEA-EDA displayed comparatively less stability. All compounds demonstrated key pharmacophoric features and lacked mutagenicity or PAINS alerts, although lactucopicrin and 11β,13-dihydrolactucopicrin showed risks for hepatotoxicity. Overall, the critical bonding and drug-like features, biological activity spectra, and favorable medicinal characteristics predict their biological behavior in laboratory testing. Although additional experimental validations are necessary, our findings indicate that the three lead compounds-namely, trans-delta-viniferin, trans-E-viniferin, and 3,4-DHPEA-EDA, isolated from traditional medicinal plants-are promising novel dual inhibitors of two critical SARS-CoV-2 proteins.