Integrated Experimental and Computational Profiling of Curcumin-Derived Diarylpentanoids Reveals Mechanistic Determinants of COX1/COX2 Inhibition and Selectivity.

The nonsteroidal anti-inflammatory drugs (NSAIDs) reduce prostaglandin E2 (PGE2) levels by inhibiting COX2. Nevertheless, many also suppress COX1, which leads to gastrointestinal side effects. Curcumin is an anti-inflammatory agent whose bioavailability is low, necessitating the development of more active and stable curcumin analogues. In this study, 43 derivatives are evaluated for their effects on PGE2 production and COX regulation in IFN-γ/LPS-stimulated RAW 264.7 macrophages, and among these derivatives, three compounds (C25, C27, and C43) demonstrated strong, dose-dependent inhibition of PGE2, with IC50 values of 6.15, 5.78, and 12.15 μM, respectively outperforming curcumin and exhibiting very low cytotoxicity (IC50 > 500 μM). Other than that, QSAR analysis revealed that the electron-withdrawing groups, aryl substitution patterns, and higher lipophilicity contribute to enhanced PGE2 inhibition. Docking showed that C25 and C43 formed hydrophobic, π-cation, and halogen interactions in COX2, which are in line with their superior biological activity. The 500 ns MD simulations demonstrated that C25 and C43 stabilized COX2 more effectively than COX1, proven by the lower RMSD, reduced residue fluctuations, and stable Rg profiles. MM/PBSA also corroborated their improved affinity, with C25 having the most desirable binding free energies with both isoforms and a clear energetic preference for COX2. Altogether, the computed and biological data all indicate that C25 and C43 have the potential as COX2-selective anti-inflammatory agents, which are more potent and selective than curcumin.