Developments and challenges in hit progression within fragment-based drug discovery

Fragment-based Drug Discovery (FBDD) is a proven methodology for the discovery of new therapeutics. After the identification of small molecular fragments, subsequent steps are guided by the “Design, Make, Test” (DMT) cycle. During the “Design” phase, chemical modifications are proposed that generate Structure-Activity Relationship information, improve interaction profiles and physicochemical properties. In the “Make” phase, designs are synthesised into viable compounds, with an emphasis on feasibility, scalability and the incorporation of novel chemistries enabling broad chemical space sampling. Finally, the “Test” phase evaluates these compounds through a series of assays, identifying binders and enabling Structure-Activity Relationship models that guide subsequent designs. Within DMT cycles, fragment progression – the process of converting initial hits into more potent follow-up lead compounds – is an essential component, but has many challenges associated with it. Here, we review such challenges along with recent developments designed to mitigate them. This review maps key bottlenecks in turning fragment hits into lead compounds and highlights emerging solutions: integrated Design-Make-Test cycles, high-throughput assays, automation and modelling to accelerate reliable hit-to-lead progression.