System Pharmacology-Driven Tri-Modal Leads Discovery of Anti-Mpox Therapeutics: Integrating Quantum Mechanics, Molecular Dynamics, and Network Topology

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The re-emergence of the Mpox virus (MPXV) as a global public health threat highlights the critical limitations of existing antivirals, which predominantly target viral replication while neglecting host-mediated immunopathology and severe clinical symptomatology. To address this therapeutic gap, we developed a system pharmacology-mediated trimodal framework from a comprehensive cheminformatics and medicinal chemistry workflow integrating quantum mechanics, molecular dynamics, network topology, and AI-driven retrosynthetic analysis. Here, we report the discovery of three unique functional leads selected via ligand-based virtual screening (LBVS) targeting the highly conserved viral VP39 methyltransferase (PDB: 8B07), a pivotal enzyme in viral mRNA cap formation and replication from a focused library enriched for structural analogs of validated inhibitors. Following viral target preparation and ligand library construction, candidates underwent molecular docking and ADMET profiling, which predicted favorable oral bioavailability and high safety margins. Electronic stability and chemical reactivity were validated via DFT frontierorbital analysis, while 200-ns MD simulations confirmed dynamic stability. Crucially, following simulation, thermodynamic efficacy for the top lead complexes was substantiated by MM-GBSA binding free energies (ΔG bind) ranging from –23.44 to –25.49 kcal mol–1, significantly outperforming the reference inhibitor. Pivotally, biological activity spectra and network pharmacology analysis revealed alongside direct viral VP39 blockade, these scaffolds exhibit a synergistic, host-directed effect polypharmacological division of labor, Lead 1 act as a potent viral egress inhibitor targeting host kinases (ABL1/SRC), Lead 2 functions as an immunomodulator via Toll-like receptor (TLR9) and GPCR pathways and Lead 3 offers a novel symptomatic management strategy by targeting voltage-gated sodium channels (SCN9A). Finally, the synthetic route prediction confirmed the translational feasibility of these candidates from commercially available precursors. This study establishes a rational, multi-scale computational strategy for discovering next-generation Mpox therapeutics that simultaneously arrest viral spread, potentiate host immunity, and alleviate debilitating symptoms.

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