MULTIPLE BINDING MODE OF REVERSIBLE SYNTHETIC THROMBIN INHIBITORS - ACOMPARATIVE STRUCTURAL-ANALYSIS

The central role of the serine protease thrombin in hemostasis and thr ombosis brought many scientists to develop highly potent and selective thrombin inhibitors. Thrombin-inhibitor complexes have extensively be en studied in order to understand structure-function relationships, an d to design new inhibitors that can be used with broader efficacy over existing antithrombotic agents. In this paper, we summarize in a comp arative manner the state of the art on reversible thrombin inhibitors and we discuss some structural aspects of thrombin-inhibitor interacti on, which account for the different affinity and potency of these mole cules. We also report here our approach to develop a new class of synt hetic, multisite-directed thrombin inhibitors, named hirunorms, design ed to mimic the distinctive binding mode of hirudin, We emphasize here that, despite the high specificity of thrombin action, the interactio n of inhibitors in its active site may occur with quite different mech anisms.