It is over 20 years since the first fragment-based discovery projects were disclosed. The methods are now mature for most ‘conventional’ targets in drug discovery such as enzymes (kinases and proteases) but there has also been growing success on more challenging targets, such as disruption of protein–protein interactions. The main application is to identify tractable chemical startpoints that non-covalently modulate the activity of a biological molecule. In this essay, we overview current practice in the methods and discuss how they have had an impact in lead discovery – generating a large number of fragment-derived compounds that are in clinical trials and two medicines treating patients. In addition, we discuss some of the more recent applications of the methods in chemical biology – providing chemical tools to investigate biological molecules, mechanisms and systems.

Fragment-based lead discovery has emerged over the past two decades as a successful approach to generate novel lead candidates in drug discovery programs. The two main advantages over conventional high-throughput screening (HTS) are more efficient sampling of chemical space and tighter control over the physicochemical properties of the lead candidates. Antibiotics are a class of drugs with particularly strict property requirements for efficacy and safety. The development of novel antibiotics has slowed down so much that resistance has now evolved against every available antibiotic drug. Here we give an overview of fragment-based approaches in screening and lead discovery projects for new antibiotics. We discuss several successful hit-to-lead development examples. Finally, we highlight the current challenges and opportunities for fragment-based lead discovery toward new antibiotics.