Hit Your Target With Fragment-based Drug Discovery

If you validated the drug target to cure a disease, but can’t hit it efficiently with high-throughput screening (HTS), fragment-based drug discovery could be your answer. It has established itself as a reliable method in identifying compounds for novel or hard to hit target classes with the registration of the skin cancer drug Zelboraf (Vemurafenib) to target B-Raf^V600E melanoma.

No doubt, HTS has lead to amazing breakthroughs in drug discovery in the past decades. However, it has its limits in the identification of protein-protein interaction inhibitors. As recently reviewed by Drysdale et al., the latest research in this field demonstrate that this is the area where fragment-based drug discovery has its clear advantages over HTS.¹ In addition, whereas the latter needs to understand and make use of the target mechanism of action to identify small molecule compounds, fragment-based drug discovery is based on a biophysical screening process: The determination of the three-dimensional experimental binding mode of low-molecular-weight ligands to its target using X-ray crystallography or NMR spectroscopy.

If your laboratory is not equipped with these fragment screening technologies, Scientist can connect you with resources and vendors such as SimBioSys and Alveus Pharma for fragment-based drug discovery to deliver the starting points for your drug discovery efforts. As these examples show, it might be worth it:

Three outstanding examples for fragment-based drug discovery

1. A good example for the reliability of the fragment-based screening method is the targeting of Hsp90. The biophysical screening method identified chemotypes comparable to the published clinical candidates.
2. More striking, whereas HTS failed to give any useful starting-points, fragment-based drug discovery has identified compounds binding directly to K-RAS, one of the most mutated and validated targets in cancer. In addition, the latter screening method required fewer compounds to be screened compared to high-throughput-screening.
3. Another convincing case for the advances of fragment-based drug discovery is the identification of compounds inhibiting ß-secretase for the potential treatment of Alzheimer’s disease. In this arena, HTS had so far produced limited results.

The list of compounds in clinical development resulting from fragment-based drug discovery is growing and the registration of Zelbraf to target B-Raf^V600E melanoma might just be the beginning of a new era in drug discovery.