Investigating the Potential of Selective COX-2 Inhibitors as Multi-Targeted Agents Against KRAS Signaling
Abstract
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.
Keywords
References
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Details
Primary Language
English
Subjects
Biomolecular Modelling and Design
Journal Section
Research Article
Publication Date
July 25, 2026
Submission Date
February 12, 2026
Acceptance Date
March 18, 2026
Published in Issue
Year 2026 Volume: 2026 Number: 2
