In contrast to high-throughput screening, which relies on vast libraries of small molecules, fragment-based drug discovery takes a different approach to identify potential starting molecules for drug development. Using libraries typically comprising just a few thousand molecules, each of <20 heavy (non‑hydrogen) atoms, fragment-based drug discovery identifies hits with varying affinity for the drug target. The hit‑molecules can subsequently be merged, linked, or expanded to transform weak binders and fragments with moderate binding affinity into high‑affinity small molecules. A major advantage of this method is that it promises higher hit rates compared to traditional small molecule screening, since the lower molecular complexity of fragments corresponds to fewer unfavorable interactions with the drug target.
Despite being driven by recent developments in screening technologies, fragment‑based drug discovery remains challenging. This is mainly due to the small size of the fragment molecules, the limited quantities of material available, and the molecular stability.
Traditional approaches to fragment‑based drug discovery rank molecules by affinity rather than kinetics. This is because fragment libraries often contain a high proportion of weak binders with very fast off‑rates that cannot be resolved by standard instrumentation. Since affinity describes the relationship between the on‑rate and the off‑rate, it does not discriminate between a hit and a non‑specific binding event. Moreover, due to the weak binding and often low purities, the signal obtained from fragments may be mistaken for affinity when no actual binding has occurred. Measuring affinity can therefore extend workflows by generating large numbers of false positive results.
Kinetic trajectory as lead matter progresses from hits to drugs, adapted from "Application of label‑free biosensing in drug discovery: The past, present and future", CHI Drug Discovery Chemistry, April 22nd 2016" by John Quinn.
Using the Creoptix™ WAVEsystem, researchers can reliably determine off‑rates of up to 10s-1, starting with just a crude reaction mixture. By adopting this approach, the occurrence of false positives is minimized. Moreover, since the off‑rate is not concentration dependent, only very small amounts of material are required to generate a comprehensive data set, making the Creoptix™ WAVEsystem ideal for fragment‑based screening. A further advantage of the Creoptix™ WAVEsystem is that it provides high sensitivity at even very low immobilization levels, significantly reducing the costs associated with obtaining purified target protein.