Phytochemical-capped silver nanoparticles as functional antiviral nanomaterials: Computational and experimental analysis of nano–bio interactions with SARS-CoV-2 targets

Abstract

The emergence of SARS-CoV-2 variants highlights the need for antiviral strategies integrating molecular inhibitors and nanostructured materials. This study employed a computational and network pharmacology approach to investigate clinically approved SARS-CoV-2 protease inhibitors (nirmatrelvir, ensitrelvir, and boceprevir) in combination with Carica papaya –functionalized silver nanoparticles (CAR–Ag NPs). Carica papaya phytochemicals regulate antiviral, anti-inflammatory, oxidative stress, and immune-related pathways and act as surface-capping agents that define CAR–Ag NP biointerface reactivity. Molecular docking showed favorable interactions with SARS-CoV-2 main protease (Mpro), viral RNA structural elements, and epidermal growth factor receptor (EGFR). Molecular dynamics simulations confirmed stable complexes over 50 ns with sustained hydrogen bonding and consistent interaction profiles. Density functional theory analyses supported electronic stability and reactivity of nanoparticle–ligand systems, while ADMET predictions indicated acceptable pharmacokinetic and safety profiles. Importantly, computational findings were supported by experimental Mpro inhibition assays of key Carica papaya flavonoids. Overall, CAR–Ag NPs act as nanomaterial interfaces that enhance multi-target interaction stability of protease inhibitors across viral and host pathways, providing a computational nanomaterials–biointerface framework for designing phytochemical-functionalized antiviral nanotherapeutics.