A Perspective on Covalent Inhibitors: Research and Development Trends of Warheads and Targets

CCovalent inhibitors are being used more frequently in drug discovery and is expected to revolutionize how enzyme inhibitors and receptor modulators are created in the future. More than 30 covalent therapies have been approved by the US FDA as a result of this approach, which has produced a wide spectrum of effective treatments. Covalent inhibitors have also made it possible to target previously neglected targets, demonstrating that covalent inhibition has a tremendous opportunity to cure human diseases. We analyzed the CAS Content Collection to examine the publishing trends of covalent inhibitors with various types of warheads and their target proteins for developing a landscape view of the research effort in this area. We identify potential substructures for specific protein targets by assessing the frequencies of specific warhead structures in covalent inhibitors. In addition, a comprehensive database of warheaded compounds and the corresponding protein targets has been collected, which may be useful for analysis of structure-activity relationships. Our work provides an overview of covalent inhibitor research and demonstrates how the power of the analysis of large data sets can accelerate research and development.