ABSTRACT
Inhibition of disease-associated enzyme targets by small molecular weight drugs is a wellestablished modality for pharmacologic intervention in human disease. Indeed, a 2007 survey of the FDA Orange Book showed that more than 300 marketed drugs work through enzyme inhibition. Among orally dosed drugs in clinical use, nearly half function by inhibition of specic enzyme targets. Likewise, much of the current preclinical drug discovery efforts in biotechnology and pharmaceutical companies-as well as those in government and academic laboratories-are focused on the identication and optimization of small molecules that function by inhibition of specic enzyme targets. The reasons for the popularity of enzymes as targets for drug discovery have been reviewed a number of times (see, e.g., Copeland 2013). In brief, enzymes make good drug targets for two signicant reasons. First, the catalytic activity of specic enzymes is often critical to the pathophysiology of the disease, such that inhibition of catalysis is diseasemodifying. Second, the binding pockets for natural ligands of enzymes play a crucial role in catalytic activity, and these pockets are often uniquely well-suited for interactions with small molecule drugs. Thus, the very nature of the chemistry of enzyme catalysis makes these proteins highly vulnerable to inactivation by small molecule inhibitors that have the physicochemical characteristics of oral drugs.
