Page - (000062) - in Biomedical Chemistry: Current Trends and Developments

Francisca Lopes, Maria M. M. Santos and Rui Moreira* 1.2 Designing Covalent Inhibitors: A Medicinal Chemistry Challenge 1.2.1 Introduction The design of enzyme inhibitors is one of the most attractive research topics in Medicinal Chemistry. In particular, covalent inhibitors provide the opportunity of combining concepts of chemical reactivity and mechanisms of organic reactions with the structural features required for optimal molecular recognition in order to obtain the appropriate reactivity and selectivity profile towards the desired enzyme target. Typically, these inhibitors present an electrophilic functionality capable of reacting irreversibly with catalytic amino acid residues containing a nucleophilic group (e.g. serine, threonine and cysteine) (Powers, 2002; Santos, 2007). In spite of its tremendous potential (Robertson, 2007; Potashman, 2009), designing selective covalent inhibitors remains a challenging task as the electrophilic groups present in many inhibitor structures can also react with other macromolecules leading to deleterious (off-target) events, or can be scavenged by ubiquitous low- molecular-weight nucleophiles such as glutathione leading to sub- optimal drug concentration at the site of action (Johansson, 2012). However, there are several examples of covalent inhibitors that are widely used drugs, including acetyl salicylic acid (the active ingredient of Aspirin), orlistat (anti-obesity drug) and ampicillin (antibiotic) (Fig. 1.2.1). Many of these drugs were not originally designed as irreversible inhibitors and their exact mechanism of action was often discovered afterwards. A recent example is the case of clopidogrel (antiplatelet agent), which was found to require activation by cytochrome P450 in the liver to generate an active metabolite containing a free thiol capable of reacting with a cysteine residue of adenosine 5´-diphosphate (ADP) receptor to form a covalent disulfide adduct (Fig. 1.2.1). Overall, nearly 30% of the enzymes that are inhibited by marketed drugs are irreversibly