Page - (000063) - in Biomedical Chemistry: Current Trends and Developments

inhibited via covalent modification, which highlights the therapeutic potential of covalent inhibitors (Robertson, 2005; Robertson, 2007; Johansson, 2012). Figure 1.2.1: Drugs acting as covalent inhibitors including their protein target(s) with active-site nucleophiles. Arrows indicate the reaction of the enzyme’s nucleophilic residue with the electrophilic site at the drug or its metabolite resulting in covalent modification of the target. 1.2.2 Designing Safer Covalent Inhibitors Several approaches have been adopted by researchers in academia and pharmaceutical companies to overcome the liabilities associated with covalent inhibitors. A widely adopted strategy to develop highly selective enzyme inhibitors has been the design of mechanism-based or suicide inhibitors (Powers, 2002; Lucas, 2013). These are substrate analogs containing a poor electrophile moiety that are activated by the catalytic machinery of the target enzyme to generate a more electrophilic species capable of reacting with a nucleophile in the active site, leading to irreversible inhibition of the enzyme. This challenging approach has led to the discovery of suicide inhibitors (Fig. 1.2.2), which are in clinical use such as vigabatrin, an anticonvulsivant agent designed to irreversibly inhibit the GABA transaminase. Other suicide inhibitors such as tranylcypromine (monoamine oxidase inhibitor, antidepressant) and selegiline (monoamine oxidase inhibitor, antiparkinsonian) had their mechanism of action discovered serendipitously.