Finding fragment hits is ultimately the product of applying optimal screening methods to a diverse, high quality fragment library.
Our dynamic collection of 1,500 – 2,000 fragments is the result of active maintenance focused on:
- Maximizing diversity using novel cheminformatic approaches
- Assessing of compound properties in relation to assay technology used for screening
- QC of the compounds and screening mixes by NMR spectroscopy
Building on carefully designed and optimized fragment screening and compound profiling assays, we take every molecule with a concentration-dependent binding effect very seriously as a potential unique starting point in your drug discovery project. Orthogonal screening maximizes the chances of finding diverse fragment hits, even against poorly ligandable targets, and efficient biophysical validation allows us to work on those chemical series that matter.
Although orthogonally validated, the most promising chemical series are often still weak in affinity. Conversion of those chemical series to functional binders with a cellular readout remains a challenge in drug discovery and is often cited as one of the main deterrents to the use of fragment-based approaches. Our medicinal chemists have learned to tackle this challenge through years of experience and are adept at:
- Interpreting biophysical data when early functional assays do not directly show an effect.
- Understanding the strengths and weaknesses of each assay in the cascade and integrating this information to gain insight into how the ligands are interacting with the target.
- Using a variety of structural information derived from competition binding, binding site mapping (via Chemical Shift Perturbation analysis in NMR), low-resolution NMR structures and high-resolution crystallographic structures to efficiently design new analogs with the desired MoA and properties.
This rich information and experience allow us to successfully traverse the gulf between the low affinity of fragment hits and early analogs to the sub-micromolar regime where compounds begin to show activity in more traditional assays. At this point, we can begin to apply assays for target selectivity, early ADME and activity in relevant cell lines.
At ZoBio, fragment evolution develops validated, low affinity binders to sub-micromolar novel lead molecules.