Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery

Fragment based drug discovery has long been used for the identification of new ligands and interest in targeted covalent inhibitors has continued to grow in recent years, with high profile drugs such as osimertinib and sotorasib gaining FDA approval. It is therefore unsurprising that covalent fragment-based approaches have become popular and have recently led to the identification of novel targets and binding sites, as well as ligands for targets previously thought to be 'undruggable'. Understanding the properties of such covalent fragments is important, and characterizing and/or predicting reactivity can be highly useful. This review aims to discuss the requirements for an electrophilic fragment library and the importance of differing warhead reactivity. Successful case studies from the world of drug discovery are then be examined.

Automated summary

Fragment-based drug discovery plays a crucial role in identifying new ligands, and there is increasing interest in targeted covalent inhibitors. Covalent fragment-based approaches have led to the discovery of novel targets and binding sites, including previously considered "undruggable" targets. Understanding the properties and reactivity of these covalent fragments is important in drug discovery.