Interactive Analysis of TX-1123 with Cyclo-oxygenase: Design of COX2 Selective TX Analogs

Background: To date, two cyclo-oxygenase (COX) isoforms, COX1 and COX2, have been identified. In the present study, the COX-inhibitory activities of TX-1123 derivatives with the 2-hydroxyarylidene-4-cyclopentene-1,3-dione structure were examined, and the binding profiles of TX-1123 to COXs were analyzed using docking simulations.

Materials and methods: X-Ray data on COX1 [protein data bank (PDB) ID=1PGG] and COX2 (PDB ID=3LN1) were used for molecular interactive simulations. The interactive profiles of TX-1123 derivatives with COXs were examined using a molecular simulation technique with Molegro Virtual Docker (CLC bio, Aarhus, Denmark).

Results: TX-1123 exhibited COX1-inhibitory activity [half-maximal-inhibitory concentration (IC₅₀)=1.57×10^-5 M]. The COX2 inhibitory activity of TX-1123 was potent (IC₅₀=1.16×10^-6 M), and the ratio of COX1/COX2 inhibition was 13.5. TX-1123 bound to the COX2 molecule, and the oxygen atom of the 4-cyclopentene-1,3-dione region of TX-1123 interacted with Cys²⁶ and Gln⁴⁴⁷ of COX2.

Conclusion: The TX-1123-binding pocket of COX2 differs from that of the COX2-selective celecoxib-binding pocket. TX-1123 exhibited a different COX2-interactive mechanism from that of celecoxib.

Protein kinase; cyclo-oxygenase; kinase inhibitor.