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The molecule under consideration, 4\u2010(4\u2010methoxyphenyl)\u20104\u2010oxobutanoic acid, is distinguished from fenbufen by the absence of the biphenyl moiety. This characteristic results in the generation of nontoxic metabolites during biotransformation. The incorporation of aromatic amino acid residues (phenylalanine and tyrosine) led to the modulation of the hybrid NSAID\u2013amino acid and NSAID\u2013peptide derivatives, thereby altering their biological activity and safety profile. The inhibitory activity against the dual cyclooxygenase\u20102\/5\u2010lipoxygenase system was evaluated using molecular docking, free energy calculations, and per\u2010residue decomposition analysis based on molecular dynamics simulations. Compounds containing a tyrosine residue or the Tyr\u2010Phe dipeptide exhibited strong drug\u2013receptor binding affinities and long\u2010term stability during our simulations, in some cases outperforming the reference drugs celecoxib and zileuton. The values of the free energy (\u0394\n                    <jats:italic>G<\/jats:italic>\n                    ) obtained through the Boltzmann equation demonstrated a strong correlation with the energy decomposition data, particularly for the lead compounds, which exhibited stabilizing interactions with the heme prosthetic group and the Fe\n                    <jats:sup>2+<\/jats:sup>\n                    ion. These findings provide substantial support for the identification of these molecules as promising candidates for further preclinical development.\n                  <\/jats:p>","DOI":"10.1002\/open.202500452","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T14:44:31Z","timestamp":1774017871000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Dual Inhibition of COX\u20102\/5\u2010LOX Through Novel Hybrids of NSAIDs and Peptides: Insights from Molecular Dynamics Simulation and Per\u2010Residue Decomposition"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6527-9204","authenticated-orcid":false,"given":"J. 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