Active-site mimetic inhibition of thrombin

The structures of two mimetic inhibitor complexes of human α-thrombin have been determined by X-ray crystallography. One mimics a β-turn with a bicyclic ring system; the other mimics two different active-site binding modes. The β-turn mimetic is used to approximate a turn found in the conformation of fibrinopeptide A, which is catalytically released by thrombin in the activation of fibrinogen to fibrin. The binding of the second mimetic is a hybrid between normal substrate and the abnormal binding of the potent natural leech inhibitor hirudin. The binding of the β-turn mimetic is tenuous, because it is like a substrate, while that of the substrate–hirudin hybrid is that of a tenacious inhibitor (which it is). Structurally retrospect modifications for rational design and improvement of both mimetic inhibitors are proposed.