text: One of the keys to developing COX-2 selective drugs is the larger active site of COX-2, which makes it possible to make molecules too large to fit into the COX-1 active site but still able to fit the COX-2. The larger active site of COX-2 is partly due to a polar hydrophilic side-pocket that forms because of substitution of Ile523, His513, and Ile434 in COX-1 by Val523, Arg513, and Val434 in COX-2. Val523 is less bulky than Ile523, which increases the volume of the active site. Substitution of Ile434 for Val434 allows the side-chain of Phe518 to move back and make some extra space. This side-pocket allows for interactions with Arg513, which is a replacement for His513 of COX-1. Arg513 is thought to be a key residue for diaryl heterocycle inhibitors such as the coxibs. The side-chain of Leu384, at the top of the receptor channel, is oriented into the active site of COX-1, but, in COX-2, it is oriented away from the active site and makes more space in the apex of the binding site.
  The bulky sulfonamide group in COX-2 inhibitors such as celecoxib and rofecoxib prevent the molecule from entering the COX-1 channel.
  For optimal activity and selectivity of the coxibs, a 4-methylsulfonylphenyl attached to an unsaturated (usually) five-membered ring with a vicinal lipophilic group is required (rofecoxib). The SOCH can be replaced by SONH, wherein the lipophilic pocket is occupied by an optionally substituted phenyl ring or a bulky alkoxy substituent (celecoxib). Within the hydrophilic side-pocket of COX-2, the oxygen of the sulfonamide (or sulfone) group interacts with Hist90, Arg513, and Gln192 and forms hydrogen bonds. The substituted phenyl group at the top of the channel interacts with the side-chains of amino acid residues through hydrophobic and electrostatic interactions. Tyr385 makes for some sterical restrictions of this side of the binding site so a small substituent of the phenyl group makes for better binding. Degrees of freedom are also important for the binding. The central ring of the coxibs decides the orientation of the aromatic rings and, therefore, the binding to COX enzyme even though it often has no electrostatic interactions with any of the amino acid residues. The high lipophilicity of the active site does require low polarity of the central scaffold of the coxibs.