High-throughput drug discovery: fragment-based screening by X-ray crystallography of the human adrenaline synthesizing enzyme PNMT

摘要

Fragment-based lead discovery is a new approach to drug design that involves screening libraries of compounds that are significantly smaller (typically 120-250 Da) than drug molecules (typically up to 500 Da). The rationale is that "drug-like" fragments represent individual binding epitopes whereas larger "drug-like" compounds found in conventional high throughput screen (HTS) libraries represent combinations of binding epitopes. Drug-like fragments that bind to proteins have lower affinities than drug-like compounds, but are more "efficient" ligands - and therefore better starting points for lead development - because a greater proportion of atoms are involved in favourable receptor contacts. Fragment libraries typically contain a few hundred fragments, whereas HTS libraries may contain hundreds of thousands of compounds.