Target deconvolution from phenotype-based drug discovery by using chemical proteomics approaches

Area of Science:

• Drug discovery and development
• Chemical biology
• Proteomics

Background:

• Phenotype-based drug discovery relies on identifying small molecule targets.
• Target deconvolution, the process of identifying these molecular targets, is a critical yet challenging step.
• Various chemical proteomics strategies exist to aid in this process.

Purpose of the Study:

• To classify and summarize direct and indirect target deconvolution approaches.
• To review current chemical proteomics strategies for molecular target identification.
• To guide the selection of appropriate deconvolution strategies based on compound characteristics.

Main Methods:

• Classification of target deconvolution strategies into direct and indirect approaches.
• Summary of the principles underlying different deconvolution methods.
• Review of chemical proteomics techniques: affinity purification, photoaffinity labeling (PAL), cellular thermal shift assay (CETSA), and activity-based protein profiling (ABPP).

Main Results:

• Target deconvolution approaches can be broadly categorized as direct or indirect.
• Chemical proteomics offers a suite of powerful tools for identifying small molecule targets.
• Specific techniques like PAL, CETSA, and ABPP provide distinct advantages for target deconvolution.

Conclusions:

• No single target deconvolution strategy is universally optimal.
• The selection of a deconvolution strategy should be tailored to the specific characteristics of the compound under investigation.
• Effective target deconvolution is essential for advancing phenotype-based drug discovery.