The rational design of the “super aspirin” Vioxx.

The molecular design of the nonsteroidal anti-inflammatory drug (NSAID) vioxx (Fig. 1 is the chemical structure of vioxx) is an elegant example of rational drug design despite the withdrawal of vioxx from the market over safety concerns. The available NSAID’s, like aspirin or ibuprofen, inhibit both cyclooxygenase (COX) enzymes COX-1 and COX-2 whereas vioxx was designed to specifically inhibit COX-2. The precise inhibition of COX-2 is advantageous because COX-2 mediates the synthesis of “bad prostaglandins” responsible for pain and inflammation, while COX-1 mediates the synthesis of “good prostaglandins” responsible for protecting the stomach lining. Therefore creating selective NSAIDs, like vioxx, that specifically inhibit COX-2 promotes pain relief but doesn’t pose a significant risk for adverse side effects such as peptic ulcers.
As I mentioned in a previous post, rational drug design is guided by the molecular structure of the enzyme active site. The creation of vioxx is a great example of drug design directed by the target enzyme active site, COX-2, as well as the off-target enzyme active site from COX-1. More specifically, vioxx assembly was guided by the structural differences between these two enzymes producing a specific inhibitor for COX-2. The major structural difference between these two enzymes is the substitution of an active site isoleucine in COX-1 with a valine in COX-2. The smaller valine side chain in COX-2 permits access to a small hydrophobic pocket in the enzyme which is blocked by the larger isoleucine side chain in COX-1 (Fig. 2 shows a space filling model of vioxx superpositioned into the active sites of COX-1 in magenta and COX-2 in grey highlighting the important difference between the two enzymes that confers vioxx's preferential binding to COX-2. Notice the clash between the vioxx phenyl ring and the COX-1 isoleucine side chain). Vioxx was designed to bind to this additional pocket enhancing its selectivity for COX-2.