A NOVEL TYPE OF STRUCTURALLY SIMPLE NONPEPTIDE INHIBITORS FOR ALPHA-CHYMOTRYPSIN - INDUCED-FIT BINDING OF METHYL 2-ALLYL-3-BENZENEPROPANOATE TO THE S-2 SUBSITE POCKET

Unexpectedly, methyl and benzyl esters of 2-allyl-3-benzenepropanoic a cid were found to be not substrates but potent competitive inhibitors for alpha-chymotrypsin. The inhibitory property of the structurally si mple nonpeptidic compounds is ascribed to their high binding affinity to the enzyme at the S-2 rather than S-1 subsite pocket. These inhibit ors exist in a flexible form in solution, but as they bind to the enzy me bulky contrained conformers present in a minute concentration play an important role, forming tighter enzyme-inhibitor complexes by bindi ng to the large hydrophobic S-2 pocket. The contrained conformers are thought to be resulted from intramolecular CH/pi interactions between a vinylic proton and the aromatic pi-electron cloud in the inhibitor m olecules. These compounds constitute novel examples of the induced-fit binding inhibitor of possibly simplest structure. (C) 1998 Elsevier S cience Ltd. All rights reserved.