Investigating the Potential of Selective COX-2 Inhibitors as Multi-Targeted Agents Against KRAS Signaling

Oncogenic RAS (rat sarcoma virus) mutations cause approximately 30% of human malignancies and initiate tumorigenesis through an autocrine feedback mechanism involving the COX-2/PGE2 (cyclooxygenase-2/prostaglandin E2) pathway. This study aims to assess the direct binding affinities and molecular interaction mechanisms of 17 distinct selective and semi-selective COX-2 inhibitors (Parecoxib, Cimicoxib, Celecoxib, Polmacoxib, Mavacoxib, Rofecoxib, etc.) with oncogenic KRAS. Molecular docking simulations were performed using the MOE 2020 (Molecular Operating Environment) program. The wild-type KRAS structure (PDB ID: 4OBE) (protein data bank), obtained by X-ray crystallography, was selected as the target protein. The docking scores (S), RMSD (root-mean-square deviation) values, and binding energies of the medicines were evaluated compared to the reference ligands guanosine diphosphate (GDP) (-6.73 kcal/mol) and guanosine triphosphate (GTP) (-6.87 kcal/mol).The docking data indicate that Parecoxib (-5.91 kcal/mol), Cimicoxib (-5.89 kcal/mol), and Celecoxib (-5.88 kcal/mol) demonstrate the highest binding affinity for KRAS oncoproteins. In line with findings from our previous study, the presence of sulfonamide/sulfonyl groups in the molecular structure and the interaction of aromatic rings with Switch I/II pockets were recognized as crucial factors for increased affinity. Additionally, Polmacoxib (-5.44 kcal/mol), which interacts with carbonic anhydrase (CA), has the potential to reduce systemic toxicity and inhibit oncogenic signaling within a more favorable therapeutic window due to its tissue-specific retention properties. Thus, these drugs exhibiting increased docking scores have been validated as potential candidates for multi-targeted anticancer approaches that target mutations considered “drug-untargetable” by affecting RAS signaling networks.