Dual Inhibition of COX‐2/5‐LOX Through Novel Hybrids of NSAIDs and Peptides: Insights from Molecular Dynamics Simulation and Per‐Residue Decomposition

The present study describes the synthesis of an analog of the anti‐inflammatory drug fenbufen, a compound which has recently attracted of renewed interest in the treatment of chronic degenerative diseases such as cancer and rheumatoid arthritis. The molecule under consideration, 4‐(4‐methoxyphenyl)‐4‐oxobutanoic 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–amino acid and NSAID–peptide derivatives, thereby altering their biological activity and safety profile. The inhibitory activity against the dual cyclooxygenase‐2/5‐lipoxygenase system was evaluated using molecular docking, free energy calculations, and per‐residue decomposition analysis based on molecular dynamics simulations. Compounds containing a tyrosine residue or the Tyr‐Phe dipeptide exhibited strong drug–receptor binding affinities and long‐term stability during our simulations, in some cases outperforming the reference drugs celecoxib and zileuton. The values of the free energy (Δ G ) 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 2+ ion. These findings provide substantial support for the identification of these molecules as promising candidates for further preclinical development.