17] Design of tight-binding human immunodeficiency virus type 1 protease inhibitors

Abstract

Most potent inhibitors of HIV-1 protease reported are peptidomimetics and are based on the transition-state mimic concept. The study of inhibitors of HIV-1 protease is a relatively new field of less than a decade. Despite this short period, the discovery of potent inhibitors has proceeded at a rapid pace, partly due to the experience of designing tight-binding inhibitors of other aspartic acid proteases. The HIV-1 protease field has relied heavily on the use of X-ray structures in optimizing old series of inhibitors. Advances have been made toward the design of totally novel structures based on enzyme–inhibitor interactions. Although great progress has been made in developing potent enzyme inhibitors, it remains to be seen whether or not these compounds will be effective in altering the course of the disease. The HIV-1 protease will serve as a way to expand the usefulness of computer modeling and in improving de novo drug design.