EXPANDING THE ENVELOPE OF STRUCTURE-BASED DRUG DESIGN USING CHEMICAL LIBRARIES - APPLICATION TO SMALL-MOLECULE INHIBITORS OF THROMBIN

The utility of directed chemical libraries for enhancing structure-bas ed drug design is presented within the context of evaluating moieties of a non-aminoacid-based inhibitor series that project into the pseudo -S-3 pocket (aryl-binding pocket) of the serine protease thrombin. A d irected library approach expanded the envelope of structure-based drug design through rapid analog synthesis and crystallographic analysis c oupled to the collection of structure-activity relationship data. This process not only produced potent moieties capable of favorably intera cting with the enzyme but also diversifed the physicochemical properti es of the active compounds. The latter point may ultimately impact the late stage discovery process as the focus begins to shift from in vit ro potency to in vivo performance optimization.