Modification-free approaches to screen drug targets at proteome level

It is of great importance to explore the on- and off-target of existing drugs and discover novel druggable targets for potential therapeutic compounds. Although the hypothesis driven biological assays based approaches have made significant contribution to the drug target discovery, recent development of mass spectrometry and high-throughput proteomics have brought the drug target screening into a new era. Chemical proteomics approaches have great potential to reveal the drug-protein interaction at proteome level. However, these methods suffer from drawbacks in the chemical derivatization of drugs. Hence, there is a demand to develop novel approaches without the covalent modification. In the last decades, a series of modification-free approaches have been emerged, coupled with the cutting-edge quantitative proteomics, enabling the unbiased large-scale drug target screening. This review will introduce two types of modification-free approaches, including stability shift based methods (CETSA, TPP, SPROX), and proteolytic digestion based methods (DARTS, pulse proteolysis, LiP). (C) 2019 Elsevier B.V. All rights reserved.