Mechanistic enzymology in drug discovery: a fresh perspective

• Published in: Nature reviews. Drug discovery Vol. 17; no. 2; pp. 115 - 132
• Main Authors: Holdgate, Geoffrey A., Meek, Thomas D., Grimley, Rachel L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2018; Nature Publishing Group
• Subjects: 631/154; 631/154/1435; 631/1647/2204; 631/45/173; 631/45/607; Biomedicine; Biotechnology; Cancer Research; Dosage and administration; Drug discovery; Enzyme inhibitors; Enzymes; Enzymology; Medicinal Chemistry; Molecular Medicine; Pharmacology/Toxicology; review-article
• ISSN: 1474-1776; 1474-1784
• DOI: 10.1038/nrd.2017.219

Key Points
The application of detailed mechanistic enzyme kinetics is vital for the characterization of enzyme targets; furthermore, it is crucial to aid in the design and prosecution of assays to effectively profile compound properties and to gain insight into the mechanism of action required for drug efficacy.
Enzyme assays are used extensively in hit identification and hit validation and for detailed characterization of the compound mechanism to guide lead optimization.
It is important to understand the limitation of IC
50
values and to more deeply probe the relationship between the molecular structures of hits and leads and their kinetics of binding, inhibition and mechanism of action.
Combining information from enzyme kinetic studies with that derived from biophysical methods can be advantageous in assessing protein quality, generating suitable assays to identify a range of desired mechanisms and to complement detailed mechanistic characterization.
The efficient use of these methods enables the identification, prioritization and progression of truly differentiated compound series that have an enhanced probability of success in translation through to the clinic as a consequence of detailed understanding of their mechanism.
Understanding the role of enzymes in disease states and the implementation of strategies to modulate their activities for therapeutic benefit remains a key focus for drug discovery. Here, Holdgate and colleagues assess the benefits of conducting and applying high-quality mechanistic enzymology studies throughout a drug-discovery programme and assess the value of combining such knowledge with orthogonal biophysical methods.
Given the therapeutic and commercial success of small-molecule enzyme inhibitors, as exemplified by kinase inhibitors in oncology, a major focus of current drug-discovery and development efforts is on enzyme targets. Understanding the course of an enzyme-catalysed reaction can help to conceptualize different types of inhibitor and to inform the design of screens to identify desired mechanisms. Exploiting this information allows the thorough evaluation of diverse compounds, providing the knowledge required to efficiently optimize leads towards differentiated candidate drugs. This review highlights the rationale for conducting high-quality mechanistic enzymology studies and considers the added value in combining such studies with orthogonal biophysical methods.