A brief introduction to chemical proteomics for target deconvolution.

Abstract

Drug-target relationships provide the basis for network-based polypharmacology, and target deconvolution is a key step in phenotypic-screening based drug discovery. Due to the complexity of the mammalian proteomics and the often-limited affinity of the lead compound, it is challenging to identify the drug targets, especially when the goal is to identify all targets. This paper attempts to provide a brief and comprehensive introduction to the various methods in chemical proteomics for target deconvolution by categorizing them into two groups: the biochemical enrichment and the proteomics-screening methods. Moreover, a brief introduction of related Mass Spectrometry techniques is also provided, together with recent progress. The data for this review were queried from Web of Science and PubMed, the keywords used were Drug targets, Target deconvolution, and Chemical Proteomics. A total of over 500 relevant articles, with a time limit from 1953 to 2022, were identified according to search strategy. Duplicate records and review articles were excluded by their titles and abstracts. Finally, we found about 120 articles matching our inclusion criteria, which covered representative research and reviews of various target discovery methods. Existing target discovery methods can be grouped into either biochemical enrichment or the proteomics-screening methods, with the recent emergence of a hybrid method combining these two such as lysine reactivity profiling. The advantage of the biochemical enrichment method is the ease of operation and the comprehensive target coverage. However, most biochemical enrichment methods require a high-affinity binding of the drug to the target proteins and cannot differentiate direct/indirect targets. The proteomics-screening methods do not require drug modification but have limited protein coverage, and most of them cannot differentiate direct/indirect targets. Although existing target discovery methods have greatly facilitated pharmacological research, each of these methods has advantages and disadvantages. New strategies/methods are needed to further improve both the coverage of the proteosome and the specificity.