Web-Based Molecular Docking Identifies Microbial Natural Products as Potential Dual Inhibitors of Host SARS-CoV-2 Entry Factors ACE2 and TMPRSS2

The necessity for broad-spectrum antiviral treatments that continue to work against new viral strains has been highlighted by the COVID-19 pandemic. By concentrating on crucial human elements involved in viral entrance, host-directed treatments present an alluring substitute for directly targeting viral proteins. Among these, the serine protease TMPRSS2 and the angiotensin-converting enzyme 2 (ACE2) are essential for coronaviruses, such as SARS-CoV-2, to enter host cells. To find microbial natural products that might bind and inhibit both ACE2 and TMPRSS2 at the same time, acting as dual-entry blockers, we used a fully web-based, in silico screening methodology in this investigation. Using RDKit, the 3D structures of nine structurally distinct microbial metabolites were created from 2D SDF files. CB-Dock2, a cavity-guided docking server, was used to perform molecular docking against ACE2 (PDB ID: 6M18) and TMPRSS2 (PDB ID: 7MEQ). Utilizing AutoDock Vina scores, binding affinities were evaluated, and the best protein–ligand complexes underwent additional analysis. Strong dual binders were defined as compounds with Vina scores of ≤ –8.0 against both targets. The best possibilities were Staurosporine (–9.3, –8.0), Rapamycin (–11.0, –8.6), and Dactinomycin (–12.5 for ACE2, –9.8 for TMPRSS2). The chemical diversity of the hits was supported by Tanimoto similarity analysis, which verified little structural repetition among the screened compounds. Venn diagrams were used to provide visual representations of binding overlap, while heatmaps were used to show structural similarities. According to this study, several microbial natural compounds may target ACE2 and TMPRSS2 at the same time, making them potential broad-spectrum antiviral leads. Researchers with little to no coding experience can replicate the computational process utilized here, which is fully web-based and accessible without the need to install software. These results highlight the potential of microbial metabolites as host-targeted antiviral medicines and lay the groundwork for additional experimental confirmation.