X-ray Facility fragment screening

The combined structural biology facilities within the Biochemistry Department (Biophysics, X-ray, NMR and Cryo-EM) have the facilities required to conduct fragment screening by a number of methods. These can be either perfomed by the users or conducted by staff within the facilities as a service.   

The Xray crystallography facility has an in-house fragment library optimised for screening by X-ray crystallography. 

Fragment library

The library is a combination of the Minifrag and Fraglight libraries developed by Astex and Martin Noble’s group in Newcastle. The Minifrag library consists of 65 very small fragments containing 5 to 7 non-hydrogen atoms. As these fragments are so small, they must be screened at appoximately 1 M in order to observe binding. To facilitate soaking these compounds at such high concentrations they are all selected to be soluble in water without the need of organic solvents such as DMSO. In our library, these compounds are supplied at 2 M concentration in order to allow soaking at 1 M in the chosen crystallization conditions. The Fraglite library consists of < 14 non-hydrogen atom fragments which are designed to explore “pharmacophore doublets”, such as a hydrogen bond acceptor (HBA) next to a hydrogen bond donor (HBD).  The Fraglite compounds also contain either a bromine or iodine: the anomalous dispersion from the halogens can then be used to help locate the fragments using crystallography. As these compounds all contain Br or I they are significantly less soluble and have higher MW than the Minifrag library. Therefore, the Fraglite compounds in our library are dissolved at 500 mM in DMSO.

The library is available in various different formats to allow flexibility in its use. The library can be used for both fragment soaking or co-crystallization depending on which method is most suitable for the project. 

Minifrag library- https://www.sciencedirect.com/science/article/pii/S1359644619300017

Fraglite library- https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00304

Xchem fragment screening 

The faciliity has extensive experience of using the XChem facililty at Diamond for high throughput fragment screening and we can be used as a base for collaborative projects. The Facility manager is a designated Super User at the Xchem facility.  

History of fragment screening at the department

The various groups have very extensive experience of fragment screening over a number of years. Indeed, Astex pharmaceuticals was originally founded out a collaboration involving Sir Tom Blundell at the Biochemistry department. A significant number of papers utilizing fragment screening have been published using the facility.