Reducing attrition early in discovery

Over the past decade fragment-based drug discovery (FBDD) has become firmly established and is now rivalling more traditional methods of hit identification, such as high throughput screening (HTS), for finding low molecular weight compounds that bind to protein targets. This widely adopted methodology delivered its first drug, Zelboraf (vemurafenib), to the market in 2011 and has generated a diverse pipeline of more than 26 clinical-stage compounds.

Unlike HTS, which screens larger, more drug-like compounds, FBDD aims to identify small chemical fragment hits, which are then combined or enlarged to produce a lead with higher affinity or tighter binding to the target. The success of FBDD in generating high-quality drug candidates results from the integration of structural biology, biophysical characterisation using techniques such as surface plasmon resonance (SPR), nuclear magnetic resonance (NMR) and X-ray, and rigorous medicinal chemistry.¹