Elucidating the Binding Behavior of Highly Potent COX-2 Selective Inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the cyclooxygenase enzymes (COXs), and are widely used for the treatment of inflammation, pain, and cancers. A selective inhibition of the COX-2 isoform is desirable, as this is overexpressed during inflammatory events. Therefore, many efforts have been directed toward the development of COX-2 selective inhibitors. Unfortunately, most of these inhibitors have been found to be highly cardiotoxic. Therefore, a deeper understanding of the molecular bases of COXs selective inhibition is of great demand. Recently, we have successfully used metadynamics to study the binding behavior of SC-558, a highly potent COX-2 selective inhibitor, in both COX-1 and COX-2. Following the line traced in our previous work, we have here extended the metadynamics studies on two highly potent COX-2 selective inhibitors, namely nimesulide and rofecoxib. Our results provide useful computational tools to design small organic molecules with fine-tuned COX-1/COX-2 potency and selectivity. Furthermore, these results can be of paramount importance in the design of less toxic novel anti-inflammatory drug candidates.