Target Engagement Assays in Early Drug Discovery

Area of Science:

• Drug Discovery and Development
• Biochemistry
• Pharmacology

Background:

• Target engagement quantification is essential for structure-activity relationships and developing potent drug candidates.
• Target engagement data supports drug mechanism of action (MoA) elucidation, potentially improving clinical outcomes.
• Numerous assays exist to assess target engagement in both isolated proteins and cellular environments.

Purpose of the Study:

• To review and summarize the diverse range of assays used for target engagement quantification.
• To highlight the importance of target engagement in drug discovery and its role in understanding drug MoA.
• To discuss the advantages, trade-offs, and target specificities of various target engagement assays.

Main Methods:

• Monitoring changes in protein stability, structure, optical properties, or mass difference upon ligand binding.
• Characterizing compounds using thermodynamic, kinetic, and structural binding parameters.
• Utilizing a variety of techniques applicable to isolated proteins and cellular systems.

Main Results:

• A wide array of assays are available for target engagement assessment.
• These methods provide critical data for structure-activity relationship (SAR) studies.
• Assays offer insights into binding thermodynamics, kinetics, and structural interactions.

Conclusions:

• The choice of target engagement assay depends on the specific protein class and experimental context.
• Diverse methodologies enable comprehensive characterization of drug-target interactions.
• Effective target engagement measurement is fundamental to successful drug discovery.