text: Studies on the binding mechanism of selective COX-2 inhibitors show that they have two reversible steps with both COX-1 and COX-2, but the selectivity for COX-2 is due to another step that is slow and irreversible and is seen only in the inhibition of COX-2, not COX-1. The irreversible step has been attributed to the presence of the sulfonamide (or sulfone) that fits into the side-pocket of COX-2. This has been studied using SC-58125 (an analogue of celecoxib) and mutated COX-2, wherein the valine 523 residue was replaced by isoleucine 523. The irreversible inhibition did not happen, but reversible inhibition was noticed. A model has been made to explain this three-step mechanism behind the inhibitory effects of selective COX-2 inhibitors. The first step accounts for the contact of the inhibitor with the gate of the hydrophobic channel (called the lobby region). The second step could account for the movement of the inhibitor from the lobby region to the active site of the COX enzyme. The last step probably represents repositioning of the inhibitor at the active site, which leads to strong interactions of the phenylsulfonamide or phenylsulfone group of the inhibitor and the amino acids of the side pocket. It is directly inhibition to postaglanding