Fragment Screening and Compound Profiling

A drug discovery campaign based on fragments will encounter a wide range of affinities from single digit mM to single digit nM or even pM. Success demands the ability to reliably detect and characterize interactions throughout this entire affinity range. At ZoBio, experience has shown us the only way to achieve this is to have many different technologies in our palette and to have a deep understanding of the strengths and weaknesses of each.

The core of our biophysical assays consists of our proprietary Target Immobilized NMR Screening (TINS) [1] technology and Surface Plasmon Resonance (SPR). Both allow sensitive, label-free detection of small molecules binding to a target and, if desired, comparison to an off-target or reference. In addition, both utilize an immobilized sample of the target which enables reliable cross-correlation of data. In contrast, TINS is sensitive to binding affinities in the range of approximately 50 µM to 10 mM while SPR is capable of detecting binding into the pM range up to about 1 mM. Parallel screening of our fragment library with both technologies provides the most complete hit discovery where the ligand efficiency of hits from either method is comparable.

Complementing biophysical methods, the ZoBio team has implemented or developed a wide variety of enzymatic assays using optical readouts. Biochemical assays can be used as part of the compound characterization cascade and/or as an orthogonal approach to screening. Through careful design of biophysical experiments and orchestration with biochemical assays, we can a priori select for hits with a desired mode of action (e.g. orthosteric vs allosteric) or binding site.

Ultimately, technology is only as good as the library that is screened. The ZoBio fragment library is a dynamic, evolving collection that reflects our continued learnings from more than 90 campaigns. It is designed for maximal coverage of fragment chemical space using proprietary cheminformatics tools while at the same time being carefully adapted to our in-house technologies. The synthetic tractability as well as the availability of close analogues (at most 3 heavy atom differences) also form part of the selection criteria. To further enhance the diversity of our screening deck, we have initiated collaborations with SpiroChem (CH) and Edelris (FR) to access the unique, 3D structures that only their experts can synthesize. We are happy to share the structures in our collection once we are under confidentiality.

Although ZoBio has been built around the concept of FBDD, we are agnostic as to the nature of hits that are fed into our compound characterization and structural biology pipeline. We have extensive experience triaging hits from HTS and encoded library campaigns and our medicinal chemists have advanced compounds from each towards IND enabling studies. To serve our client’s best interest we have teamed up with Axxam (IT) to provide a seamlessly integrated fragment/HTS approach that combines the true best of both worlds.

[1] – Marquardsen et al., J. Magn. Reson., 2006 v.182, p.:55-65