Enzymes as drug targets

"Enzymes catalyze multistep chemical reactions and achieve phenomenal rate accelerations by matching protein and substrate chemical groups in the transition state. Inhibitors that take advantage of these chemical interactions are among the most potent and effective drugs known. Recently, three new enzyme targets have been validated by FDA approval of new enzyme inhibitor drugs. These include mitogen-activated protein kinase, renin, and dipeptidyl peptidase IV. The drugs against these enzymes engage important enzyme functional groups, such as the active site serine in dipeptidyl peptidase IV."

There are more of them out there than we might imagine, and irreversible inhibitors are not always that bad.

"Some evidence now indicates that irreversible receptor protein-tyrosine kinase inhibitors might have advantages over reversible inhibitors in circumventing acquired resistance. The receptor protein-tyrosine kinases undergo ligand binding, homo-dimerization, hetero-dimerization, and internalization, whereas the intracellular nonspecific protein-tyrosine kinases lack these physiological processing events. Investigators speculate that reversible inhibitors may dissociate during receptor dimerization and internalization, and that significant signal trafficking can occur during the internalization.

By contrast, irreversibly inhibited receptor protein-tyrosine kinases would maintain inhibition throughout receptor recycling. Mutations that enhance receptor internalization would generate resistance to reversible inhibitors, but not to irreversible inhibitors. This is an interesting concept that remains to be explored.