How does Zenobia design it's shape diverse mixtures?
July 27, 2017
Why Screen as Mixtures?
In many cases, it is much more efficient to screen as mixtures because it pares down the dataset to a manageable range. One uses screening mixtures by soaking the crystal in a cocktail with multiple ligands. The secret to designing the proper mixture is to ensure that each ligand in the cocktail is differentiable from the other ligands, even at low resolutions. Express-Zen-Core288™ has a very high shape diversity, making it possible to group into shape diverse mixtures that can be distinguished at 2.7Å-3.0Å.
How Does Zenobia Make it's Mixtures?
Zenobia's mixtures for crystallographic screening contain up to 6 compounds that are highly shape diverse permitting identification of the hit from the shape of the electron density map (Nienaber et al., 2000). For those that are not limited by crystals or beamtime, mixtures of 3 or single compound screening kits are also available for crystallography. Sample mixtures of 6 are depicted below.
Examples of three of the shape diverse mixtures of 6 in Zen-Core288™.
To prepare these mixtures, the Express-ZenCore288™ collection was sorted based upon Murcko core and further grouped by Murcko cores with the same shape (e.g. benzyl and pyrimidyl). The collection contains 8 brominated and 1 iodinated compounds which were placed in separate mixtures to further enhance diversity. Express-Zen-Core288™ has a high core/shape diversity built in to increase the likelihood of a hit. This characteristic allows definition of highly diverse mixtures.
How does Zenobia Validate its Mixtures?
To validate the mixtures, 3D coordinates were generated, energy minimized and sorted into the 48 mixtures of six. PDB structures were overlaid and visually examined to ensure the compounds could be distinguished by visual examination. These PDB files are available as part of the Express-Core288™ package to enable rapid structure determination.
References:
Nienaber, Vicki et. al (2000). Discovering novel ligands for macromolecules using X-ray crystallographic screening. Nat Biotechnol. 2000 Oct;18(10):1105-8.
