Abstract

Screening fragments enables coverage of diverse chemical space with a
small library of compounds, and can identify hit matter for challenging
targets, even in cases where an HTS campaign has failed. Fragment hits are
often weak binders; however, they are a ligand efficient starting point for
medicinal chemistry, and give many options for lead development.

Here we present the fragment screening strategy
at the CRUK Beatson Institute, including fragment library design and maintenance,
utilising biophysical techniques such as SPR and NMR for primary screening and the
importance of hit validation with orthogonal methods. We present hit rates
across a range of target classes such as protein-protein interactions,
DNA-binding proteins, and GTPases, and discuss cases where low affinity
fragment hits have been developed into nanomolar inhibitors.