Protein exosites as drug targets: from structural topology to therapeutic modality

Bivalirudin's FDA approval (2000) validated bivalent thrombin inhibition via simultaneous engagement of the catalytic site and exosite I as a route to selective anticoagulants. Yet clinical translation of exosite targeting has largely remained confined to coagulation. ExositeDB, to our knowledge the first systematic catalog, highlights patterns that help explain this gap. Exosites serve diverse functions, most commonly recognition, regulation and recruitment; but many present shallow, solvent-exposed topographies that challenge conventional small molecules. This review examines what made thrombin's exosites druggable, why other targets remain preclinical and how bitopic ligands, macrocycles and proximity-inducing modalities could extend this approach beyond anticoagulation.