Chapter 8 - Enzymology in drug discovery

Abstract

Current drug discovery and development efforts focus on enzyme targets since small-molecule enzyme inhibitors have been successful therapeutically and commercially. To conceptualize different types of inhibitors and to inform the design of screens to find desired mechanisms, it can be helpful to understand the progression of an enzyme-catalyzed reaction. This data enables the complete assessment of a variety of compounds and provides the knowledge needed to effectively optimize leads toward distinctive candidate medications. Drugs interact with their intended target to produce the desired phenotypic effect, which lessens the symptoms of the disease. To inform structure-activity relationship (SAR)-guided medicinal chemistry, affinity measurements (such as IC50) have traditionally led the majority of lead optimization activities. By combining this parameter with the idea of target vulnerability, therapeutic window, small molecule’s pharmacokinetic profile, and estimates of endogenous ligand and target turnover, it is possible to create a realistic model of the system that can be used to make dosing and optimization decisions. This chapter emphasizes the need for high-quality mechanistic enzymology investigations and the benefits of combining them with orthogonal biophysical approaches.