Understanding the Dual Inhibition of COX-2 and Carbonic Anhydrase-II by Celecoxib and CG100649 Using Density Functional Theory Calculations and other Molecular Modelling Approaches

Recent developments in the dual inhibition studies of cyclooxygenase-2 (COX-2) and carbonic anhydrase (CA-II) imply a promising platform for the development of new generations of nonsteroidal anti-inflammatory drugs (NSAIDs). CG100649 is such a molecule that got recently approved by Korean Ministry of Food and Drug safety (MFDS) and is being marketed by the name polmacoxib for the treatment of osteoarthritis. CG100649 significantly inhibits CA-II in blood and COX-2 in inflammatory tissues. However, the mechanism of CG100649 dual inhibition of COX-2/CA-II is not well understood. In this study, we employed well known methods like pharmacophore modelling, a DFT based quantum chemical descriptors analysis, and molecular docking to explore the chemical features and to understand the binding behaviour of CG100649 along with other COX-2/CA-II dual inhibitors. The HOMO-LUMO and docking results indicated the prominent role of aryl sulphonamide in CG100649. The aryl sulphonamide moiety formed T-shaped Π…Π interactions with His94 in the CA-II active site, which was not observed in the case of celecoxib. Other crucial interactions were also observed which may aid in further understanding the action of dual inhibitors of this class.