Introduction: This study extends a previously developed nanobiotechnological antiviral platform based on β-escin–functionalized gold and silver nanoparticles (AuNPs and AgNPs) by incorporating rutin, a flavonoid with established antioxidant and antiviral activity. The objective was to determine whether dual phytochemical functionalization enhances molecular interactions and inhibitory potential against key SARS-CoV-2 targets. Methods: Molecular docking and 100-ns molecular dynamics simulations were conducted using AutoDock Vina and GROMACS 2023 to investigate the binding behavior, stability, and affinity of β-escin- and rutin-conjugated AuNPs and AgNPs against seven SARS-CoV-2 proteins. These included five spike protein variants (Alpha, Beta, Gamma, Delta, and Omicron), the main protease (Mpro), and RNA-dependent RNA polymerase (RdRp). Results: Both nanoparticle systems demonstrated strong and stable multi-target interactions. AuNP conjugates showed higher affinity toward spike–ACE2 complexes (binding free energy ≈-0.17 kcal/mol), whereas AgNPs preferentially interacted with RdRp (≈-0.13 kcal/mol). β-Escin exhibited the most pronounced binding across targets, particularly against Mpro (β-escin-AuNP: -9.02 kcal/mol; β-escin-AgNP: -9.04 kcal/mol), engaging key catalytic residues such as His41. Although rutin displayed slightly lower affinities (-7.35 to -8.78 kcal/mol), it complemented β-escin by occupying alternative binding sites and contributing stabilizing hydrogen bonds and π–π interactions. Dual β-escin-rutin functionalization enhanced complex stability, reduced RMSD fluctuations, and expanded antiviral coverage across all tested variants. Discussion: The observed synergistic effects between β-escin and rutin highlight the advantage of dual phytochemical functionalization, which enables complementary binding mechanisms, improved conformational stability, and broader antiviral activity against diverse SARS-CoV-2 targets. Conclusion: The β-escin–rutin–functionalized gold and silver nanoparticle system exhibits enhanced stability and multi-target inhibitory potential against SARS-CoV-2, supporting its translational potential as an intranasal nanotherapeutic strategy for COVID-19 prevention and treatment.
Zatla et al. (Wed,) studied this question.