Fragment-based screening is now well-established as a powerful approach to early drug ("lead") discovery.
This is a cysteine-specific covalent library. The electrophilic 'warheads' of the fragments are either acrylamides or chloroacetamides (25% and 75% of the library, respectively). These functional groups were selected for the construction of the library because they are in a reactivity 'sweet spot', as well as showing selectivity in chemical proteomic screens. 92% of the fragments have a MW below 300 Da, including the electrophilic functional group; 95% have fewer than 20 heavy atoms (excluding the electrophilic FG) and they also adhere to the 'rule of three'. The library has been extensively used in MS labelling fragment screens, but also in X-ray screens with success.
If you wish to use the library please contact Nir London and his group at the Weizman Institute, Israel well ahead of the screen, detailing your project and the target being investigated. This will allow Nir's group to conduct the high-throughput Mass Spectrometry screen first, and then XChem to obtain structural confirmation of the compounds that show the best MS labelling data.
In terms of support, all the fragments are commercially available. Further Mass-directed screen and covalent docking of follow up compounds can potentially be organised, although this needs to be discussed with Nir London.
SMILES: click to download the Cysteine Covalent plate map.
Resnick, E., et al. Rapid covalent-probe discovery by electrophile fragment screening. JACS, 2019, 141, 22, 8951-8968. link to paper
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