SYNTHESIS OF PEPTIDE-NSAID HYBRID COMPOUNDS AND THEIR SELECTIVITY IN INHIBITING THE DUAL COX-LOX SYSTEM DESCRIBED THROUGH DOCKING AND MOLECULAR DYNAMICS

Emerging diseases such as COVID-19 and those of significant public health concern, like rheumatoid arthritis (RA), asthma, Alzheimer’s and parkinson’s diseases, cause hyperinflammation inducing the expression and activation of the isoenzyme cyclooxygenase 2 (COX-2). COX-2 and 5-lipoxygenase both produce thromboxanes and leukotrienes that induce cytokine expression such as tumor necrosis factor alpha (TNF-α) and interlucins (IL-1ß, IL-6). Therefore, one strategy to combat exacerbated inflammation is to develop molecules that inhibit the COX-2/5-LOX system by coupling NSAID structures with amino acids, peptides, or peptidomimetic compounds. The current research reports the synthesis of hybrid compounds involving 4-(4-methoxyphenyl)-4-oxobutanoic acid, an analog of the NSAID fenbufen obtained through Heck coupling, with the aromatic dipeptides Tyr-Tyr, Phe-Tyr, Tyr-Phe y Phe-Phe. Furthermore, molecular docking studies of the obtained compounds showed binding energies of approximately -11.01 kcal/mol (NSAID-Tyr-Phe), comparable to the reference drug celecoxib and superior to diclofenac. Similarly, the compound NSAID-Phe-Tyr demonstrated a binding energy of -9.2 kcal/mol, which was superior to the reference drug Zileuton. The most successful results revealed stability in the molecular dynamics trajectories executed in NAMD and excellent binding free energies (-33.91 kcal/mol) calculated using gmx_MMPBSA, which enabled a detailed analysis of the energy contribution of each amino acid in the catalytic site.