{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:37Z","timestamp":1787028577625,"version":"build-2736575974"},"reference-count":183,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 (\u03c4 &lt; 50 ns) to slow (\u03c4 &gt; 150 ns) timescales, with unsaturated fatty acids demonstrating superior binding affinities (\u0394G = \u22126.85 \u00b1 0.27 kcal\/mol vs. \u22126.65 \u00b1 0.25 kcal\/mol for saturated analogs, p = 0.002). Arachidonic acid achieved optimal SwissDock affinity (\u22127.28 kcal\/mol), while oleic acid exhibited top-ranked predicted binding affinity within the computational hierarchy (\u0394Gbind = \u221224.12 \u00b1 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\u201380% contribution), complemented by hydrogen bonds as transient directional anchors. Comprehensive ADMET profiling predicted favorable safety profiles compared to synthetic antivirals, with \u03c9-3 fatty acids showing minimal nephrotoxicity risks while maintaining excellent intestinal absorption (&gt;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.<\/jats:p>","DOI":"10.3390\/ijms27010402","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T15:30:32Z","timestamp":1767195032000},"page":"402","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Natural Fatty Acids as Dual ACE2-Inflammatory Modulators: Integrated Computational Framework for Pandemic Preparedness"],"prefix":"10.3390","volume":"27","author":[{"given":"William D.","family":"Lituma-Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"Siddha Vetha Multiversity, 211 Warren St., Newark, NJ 07103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5878-8679","authenticated-orcid":false,"given":"Santiago","family":"Ballaz","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Universidad del Esp\u00edritu Santo, Guayaquil 0901-952, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7504-6666","authenticated-orcid":false,"given":"Tanishque","family":"Verma","sequence":"additional","affiliation":[{"name":"Siddha Vetha Multiversity, 211 Warren St., Newark, NJ 07103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1245-4109","authenticated-orcid":false,"given":"J. M.","family":"Sasikumar","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Karpagam Academy of Higher Education, Coimbatore 641021, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanmugamurthy","family":"Lakshmanan","sequence":"additional","affiliation":[{"name":"Siddha Vetha Multiversity, 211 Warren St., Newark, NJ 07103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"key":"ref_1","unstructured":"Michaud, A., Stawicki, S.P., and Izurieta, R. (2023). Perspective Chapter: Emerging Infectious Diseases as a Public Health Problem. Global Health Security\u2014Contemporary Considerations and Developments, IntechOpen."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Rezaei, N. (2023). Emerging Viral Infections in Human Population. 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