Covalent modification as a strategy to block protein-protein interactions with small-molecule drugs.

It is generally difficult to block protein-protein interactions with small-molecule drugs. A novel pharmaceutical development strategy to block protein interactions is emerging: targeted covalent modification to sterically block interactions. By this approach, compounds first interact non-covalently with a specific target protein. This interaction juxtaposes a weakly reactive group of the drug with a target amino acid sidechain, which then react by virtue of their high local concentration.