More than 40 approved drugs posses covalent mechanism of action, the interest for discovery of novel entities has recently increased. High efficiency, selective binding to rare and specific targets, and longer duration of action are main advantages of covalent modifiers. To be efficient for early stage drug discovery, covalent modifiers have to integrate novel scaffolds and easy, potentially enumerated setups. Exploring a 3,000,000 fragment space of REAL arrays (REAL - REadily AccessibLe), we have established sets of fragment-like covalent modifiers containing commonly employed binding motifs of boronic acid, acrylamide, and sulfonyl fluoride.<br/>We have shown applicability of the sulfonyl fluoride set to identify protease inhibitors. Docking screen against a model protease, trypsin, parallel synthesis of selected virtual hits followed by <i>in vitro </i>assays identified two potent hit compounds.

REAL fragment-like covalent modifiers: N-arylsulfamoylbenzenesulfonyl fluorides as potent protease inhibitors

254th National Meeting (2017)

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