Fragment-based screening is now well-established as a powerful approach to early drug ("lead") discovery.
For these 2 libraries CompChem and Synthesis support on crystal hit follow-up is available, either internally (DSiP), with Pharmenable, or with the chemical supplier Enamine.
If you would like to use the Kidd3D library, please contact Pharmenable ahead of the screen
We also have the following libraries available, however we won't be able to offer as much support:
Please contact Prof. Adam Nelson ahead of the screen.
Please contact Edelris and agree with the terms ahead of the screen
DSPL is a poised fragment library to allow rapid, cheap follow-up synthesis to provide quick SAR data. "Poised" fragments contain at least one functional group which can be synthesised using a robust, well-characterised reaction. Reactions include amide couplings, Suzuki-type aryl-aryl couplings and reductive aminations. The library was designed by analysing all of commercially available fragment space for poised-ness and selecting a chemically diverse subset.
For one challenging target, the second bromodomain of PHIP, the first ever reported hits were obtained by XChem screening; two hits were poised and were followed up accordingly, yielding compounds with improved potency in the sub-100uM range and showing good ligand efficiency - and of course detailed structural data.
More detail on the design and utility of the library can be found in our publication:
O. B. Cox, K. Krojer, P. Collins, O. Monteiro, R. Talon, A. Bradley, O. Fedorov, J. Amin, B. D. Marsden, J. Spencer, F. von Delft, P. E. Brennan, A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain. Chem. Sci., 2016, 7, 2322-2330.
UPDATE - December 2017:
The original DSPL fragment library has been replaced by a second generation poised library: DSiP provided by the chemical supplier Enamine (www.enamine.net). It is also available to purchase in a screening format. The same criteria were applied for the design of this new library 2/3 of the fragments are different from the DSPL. For previous users, see below the files attached that will help you sort compounds (un)availability in the new DSiP set. One of the main advantage is that all the compounds are available to purchase with Enamine as well as closely related compounds for a quick SAR.
Although only available in DMSO, it is possible to request a copy of the library in a different solvent (e.g. ethylene glycol) to Enamine (expect a month leadtime for delivery).
For users that have done a screen using the original DSPL library and wanting to compare both DSPL and DSiP libraries, see documents below:
- Original DSPL library (xlsx)
- Spreadsheet showing which compounds from the DSPL library are in the new DSiP library and in which well of the 1536 plate (xlsx)
- Spreadsheet showing the compounds in both DSiP and DSPL (xlsx)
- Spreadsheet showing the compounds in DSiP but not in DSPL (xlsx)
- Spreadsheet showing the compounds in DSPL but not in DSiP (xlsx)
Kidd 3D Library
This library is a DOS (Diversity Oriented Synthesis) library designed by the Spring group in the University of Cambridge. It relies on two main ideas:
From this innovative approach a spin-out company, Pharmenable, was created to design, validate and synthesis lead molecules to accelerate the early Drug discovery stages.
For more infomation: paper coming soon, and website.
Leeds 3D library
This library was designed by the Nelson and Marsden groups (University of Leeds) to allow the efficient exploration of chemical space. Fragments in this library have the following features:
These fragments were prepared by a concise 'top down' synthetic approach (see references below) and have proven to be productive in the identification of distinctive hits at Diamond.
For more information:
"Realisation of small molecule libraries based on frameworks distantly related to natural products" A. Aimon, G. Karageorgis, J. Masters, M. Dow, P. G. E. Craven, M. Ohsten, A. Willaume, R. Morgentin, N. R. -L., H. Lemoine, T. Kalliokoski, A. J. Eatherton, D. J. Foley, S. P. Marsden and A. Nelson, Org. Biomol. Chem. 2018, 16, 3160-3167 (link)
"Synthesis and Demonstration of the Biological Relevance of sp3‐rich Scaffolds Distantly Related to Natural Product Frameworks" D. J. Foley, P. G. E. Craven, P. M. Collins, R. G. Doveston, A. Aimon, R. Talon, I. Churcher, F. von Delft, S. P. Marsden, A. Nelson, Chem. Eur. J. 2017, 23, 15227-15232 (pdf)
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