LOCATING AND CHARACTERIZING BINDING-SITES ON PROTEINS

This review article begins with a discussion of fundamental difference s between substrates and inhibitors, and some of the assumptions and g oals underlying the design of a new ligand to a target protein. An ove rview is given of the methods currently used to locate and characteriz e ligand binding sites on protein surfaces, with focus on a novel appr oach: multiple solvent crystal structures (MSCS). In this method, the X-ray crystal structure of the target protein is solved in a variety o f organic solvents. Each type of solvent molecule serves as a probe fo r complementary binding sites on the protein. The probe distribution o n the protein surface allows the location of binding sites and the cha racterization of the potential ligand interactions within these sites. General aspects of the application of the MSCS method to porcine panc reatic elastase is discussed, and comparison of the results with those from X-ray crystal structures of elastase/inhibitor complexes is used to illustrate the potential of the method in aiding the process of ra tional drug design.