text: The design of covalent drugs requires careful optimization of both the non-covalent binding affinity (which is reflected in K) and the reactivity of the electrophilic warhead (which is reflected in k).
  The initial design of TCIs involves three key steps. First, bioinformatics analysis is used to identify a nucleophilic amino acid (for example, cysteine) that is either inside or near to a functionally relevant binding site on a drug target, but is rare in that protein family. Next, a reversible inhibitor is identified for which the binding mode is known. Finally, structure-based computational methods are used to guide the design of modified ligands that have electrophilic functionality, and are positioned to react specifically with the nucleophilic amino acid in the target protein.
  Targeted covalent photoisomerizable ligands (photoswitches) have been developed to remotely and reversibly control the activity of receptor proteins with light. They have been used as molecular prostheses to restore visual input in the retina and auditory input in the cochlea via glutamate receptors. Ligand conjugation is targeted to specific lysine residues via an affinity labeling mechanism.