Tools for fragment based drug discovery

Hit to Lead Development

< Structrual Biology


Fragment-based drug discovery has proven to be a valuable and complementary technique to HTS, particularly for delivering compounds against challenging targets such as protein – protein interactions and proteases. However, the early stages of evolving the weak, often mM, hits derived from fragment screens can be particularly challenging.


In many cases corporations have been structured to efficiently evolve µM hits typically derived from HTS. Moreover, medicinal chemists are often more experienced in working with these compounds. As a result, early stage compounds from FBDD efforts may be underutilized.

In order to avoid this situation, ZoBio offers complete, turnkey hit-to-lead projects. Our in-house fragment library consists of commercially available compounds that we can readily follow-up with and quantitatively assay analogues for binding using any of the techniques described previously.

The figure on the right shows the endpoints of a typical hit-to-lead project on a protein-protein interaction target. During evolution of two chemically different fragment hits, potency and ligand efficiency (LE = ΔGbind / heavy atom count) were simultaneously improved (structures for ZB1142 and analogues are shown below).



Output of a Hit to Lead project includes:
  • Orthogonally validated fragment hits against the target.
  • A predetermined number of independent series with best potency in the low µM to mid nM range (lead-like compounds) and complete SAR analysis.
  • Validated biophysical assays.
  • Where appropriate structural biology enabled (X-ray or NMR)

ZoBio has entered a strategic alliance with Mercachem, a company specialized in exclusive synthetic chemistry to support drug discovery programs. Mercachem is an industry leader in providing creative solutions to synthetic chemistry challenges and has extensive experience in working with fragments. Together, ZoBio and Mercachem present an integrated capability to rapidly advance weakly binding fragment hits into leads with optimal ADME properties. Our close proximity and similarity of vision enable this true alliance.

< Structrual Biology