Opportunities for Accelerating Drug Discovery and Development by Using Engineered Drug-Metabolizing Enzymes

Abstract

The study of drug metabolism is fundamental to drug discovery and development (DDD) since by mediating the clearance of most drugs, metabolic enzymes influence their bioavailability and duration of action. Biotransformation can also produce pharmacologically active or toxic products, which complicates the evaluation of the therapeutic benefit vs. liability of potential drugs, but also provides opportunities to explore the chemical space around a lead. The structures and relative abundance of metabolites are determined by the substrate and reaction specificity of biotransformation enzymes and their catalytic efficiency.Preclinical drug biotransformation studies are done to quantify in vitro intrinsic clearance to estimate likely in vivo pharmacokinetic parameters, to predict an appropriate dose, and to anticipate interindividual variability in response, including from drug-drug-interactions. Such studies need to be done rapidly and cheaply, but native enzymes, especially in microsomes or hepatocytes, do not always produce the full complement of metabolites seen in extrahepatic tissues or preclinical test species. Furthermore, yields of metabolites are usually limiting.Engineered recombinant enzymes can make DDD more comprehensive and systematic.Additionally, as renewable, sustainable and scalable resources, they can also be used for elegant chemoenzymatic, synthetic approaches to optimize or synthesize candidates as well as metabolites. Here we will explore how these new tools can be used to enhance the speed and efficiency of DDD pipelines, and provide a perspective on what will be possible in the future. The focus will be on cytochrome P450 enzymes to illustrate paradigms that can be extended in due course to other drug-metabolizing enzymes. Significance statementProtein engineering can generate enhanced versions of drug-metabolizing enzymes that are more stable, better suited to industrial conditions and have altered catalytic activities,