Early-stage drug discovery involves the discovery of “hits” that affect the function of a drug target in disease states, subsequently undergoing a hit-to-lead development process prior to human testing and approval. Traditional high throughput screening (HTS) methods involve testing millions of molecules for binding to protein drug targets using biophysical, biochemical, and in silico assays. These methods rely heavily on robotic automation.

As an alternative to HTS, fragment screening has been increasingly employed for hit discovery in the last few decades. While HTS uses small molecules with drug-like molecular weights (~500 Daltons), fragment screening starts with smaller ligands (150-300 Daltons) that are developed into larger leads. Seven fragment-derived drugs are currently approved for human use.

Fragment libraries are smaller and simpler, making them more accessible. The hit rate in a fragment-based screening approach is typically higher, providing more starting points for lead development with smaller libraries. Fragment binding may be especially valuable to target protein-protein interactions, making them useful for previously intractable drug targets. The discovered hits have a weak binding affinity (uM-mM) and require sensitive techniques for detection. However, detectable fragment hits frequently display good pharmacological properties, providing ideal starting points for lead development.

Fragment-to-lead development involves merging, linking, or growing fragment hits, often aided by 3D structure information of fragment-protein interactions obtained through X-ray crystallography and NMR. This Methods Collection aims to compile the techniques used in a fragment-based drug discovery approach, from library design, screening, and validation to fragment-to-lead development.