STRUCTURE-BASED DESIGN OF AN INHIBITOR MODELED AT THE SUBSTRATE ACTIVE-SITE OF ALDOSE REDUCTASE

This study presents the first successful example of structure-based dr ug design on aldose reductase in the extant literature. Starting from the structure of the modeled complex of aldose reductase with a pyrida zinone acetic acid inhibitor that we previously disclosed, using the t ools of molecular modeling for structure manipulation and molecular me chanics for energy minimization, we were able to design and synthesize a new analog that showed remarkably improved activity. We hope that a proper account of the most important enzyme-inhibitor interactions re vealed by this study will allow, in the future, the design of new lead compounds having structures unrelated to carboxylic acids. (C) 1997 E lsevier Science Ltd.