DOCKovalent is an adaptation of the DOCK virtual screening software to be able to screen covalent inhibitors for a given protein structure. So far it was applied to discover covalent inhibitors of three therapeutic targets, AmpC β-lactamase, and the kinases RSK2 and JAK3. In all cases the hit-rates were high (5/6, 5/8 and 9/15 respectively) and the best inhibitors had better than 50nM potencies against their targets. Crystal structures of AmpC and RSK2 in complex with the new inhibitors confirmed the docking predictions accuracy; cellular experiments illustrated biological utility and counter screening demonstrated exquisite selectivity of the molecules. For JAK3 these are the
first reversible covalent molecules ever reported. Encouraged by the performance of this method, in subsequent (unpublished) work it was (successfuly) used for several additional targets.

Covalent Docking