Natural Fatty Acids as Dual ACE2-Inflammatory Modulators: Integrated Computational Framework for Pandemic Preparedness

The COVID-19 pandemic exposed critical vulnerabilities in single-target antiviral strategies, highlighting the urgent need for multi-mechanism therapeutic approaches against emerging viral threats. Here, we present an integrated computational framework systematically evaluating natural fatty acids as potential dual ACE2 (Angiotension Converting Enzyme 2)-inflammatory modulators; compounds simultaneously disrupting SARS-CoV-2 viral entry through allosteric ACE2 binding while suppressing host inflammatory cascades; through allosteric binding mechanisms rather than conventional competitive inhibition. Using molecular docking across eight ACE2 regions, 100 ns molecular dynamics simulations, MM/PBSA free energy calculations, and multivariate statistical analysis (PCA/LDA), we computationally assessed nine naturally occurring fatty acids representing saturated, monounsaturated, and polyunsaturated classes. Hierarchical dynamics analysis identified three distinct binding regimes spanning fast (τ < 50 ns) to slow (τ > 150 ns) timescales, with unsaturated fatty acids demonstrating superior binding affinities (ΔG = −6.85 ± 0.27 kcal/mol vs. −6.65 ± 0.25 kcal/mol for saturated analogs, p = 0.002). Arachidonic acid achieved optimal SwissDock affinity (−7.28 kcal/mol), while oleic acid exhibited top-ranked predicted binding affinity within the computational hierarchy (ΔG_bind = −24.12 ± 7.42 kcal/mol), establishing relative prioritization for experimental validation rather than absolute affinity quantification. Energetic decomposition identified van der Waals interactions as primary binding drivers (65–80% contribution), complemented by hydrogen bonds as transient directional anchors. Comprehensive ADMET profiling predicted favorable safety profiles compared to synthetic antivirals, with ω-3 fatty acids showing minimal nephrotoxicity risks while maintaining excellent intestinal absorption (>91%). Multi-platform bioactivity analysis identified convergent anti-inflammatory mechanisms through eicosanoid pathway modulation and kinase inhibition. This computational investigation positions natural fatty acids as promising candidates for experimental validation in next-generation pandemic preparedness strategies, integrating potential therapeutic efficacy with sustainable sourcing. The framework is generalizable to fatty acids from diverse biological origins.