Covalent drugs can cause subtle changes in active sites resulting in reduced occlusion of existing pockets, and more profound shifts leading to cryptic pocket formations at protein surfaces. These remodelings may manifest ortho- or allosterically.
This review highlights the roles of nitriles in covalent inhibitors, their reactivity, examples of pharmaceuticals containing the cyano group and recent developments of nitrile-based inhibitors.
A piperidine-catalyzed Knoevenagel condensation between (hetero)aromatic aldehydes 1a–i and 2-cyanoacetamide 2a was developed to efficiently afford (E)-2-cyano-3-(het)arylacrylamides 3a–i in 40–95% yields under mild and environmentally benign conditions.
Iterative covalent drug design and discovery combining computational, synthetic, and biophysical chemistry.
A newly derived implicit equation and a new modelling method, EPIC-CoRe, allow for complete kinetic evaluation of reversible covalent inhibitors from time-dependent IC50 data.