In Silico Evaluation of Curcuma longa Curcuminoids as Dual (COX-2) / (5-LOX) Inhibitors

Inflammation is a major contributor to chronic diseases, including diabetes, cancer, and cardiovascular disorders, and is regulated by the arachidonic acid cascade through cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). Conventional anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, are associated with gastrointestinal, cardiovascular, and renal toxicities. Moreover, selective COX-2 inhibition may induce the "arachidonic acid shunt," increasing leukotriene production via the 5-LOX pathway. Consequently, simultaneous inhibition of COX-2 and 5-LOX represents a promising therapeutic strategy. This study employed in silico methods to evaluate the dual inhibitory potential of curcumin, demethoxycurcumin (DMC), and bis-demethoxycurcumin (BDMC) from Curcuma longa against COX-2 (PDB: 5F19) and 5-LOX (PDB: 7TTK), using celecoxib, ibuprofen, licofelone, and zileuton as reference drugs. Molecular docking was performed using Molegro Virtual Docker following protocol validation (RMSD < 2.0 Å), while binding interactions and pharmacokinetic properties were analysed using Discovery Studio, SwissADME, and pkCSM. Curcumin demonstrated the strongest dual inhibitory activity, with MolDock scores of −133.272 kcal/mol for COX-2 comparable to celecoxib (-138.129 kcal/mol), −143.172 kcal/mol for 5-LOX superior to zileuton (-88.474 kcal/mol), and formed hydrogen bonding, electrostatic, and hydrophobic interactions with ARG-61, GLU-465, GLN-437, and ARG-438 residues. Bis-demethoxycurcumin also exhibited favourable dual binding affinity (−127.373 and −122.126 kcal/mol for COX-2 and 5-LOX). All three curcuminoids complied with Lipinski's Rule of Five, showed good gastrointestinal absorption, and were predicted to be non-mutagenic and non-hepatotoxic, although CYP3A4 inhibition warrants further investigation.