Structure based drug design for insulin degrading enzyme (IDE)

Abstract

Insulin-degrading enzyme (IDE) is an allosteric Zn +2 metalloprotease involved in the degradation of many peptides including amyloid beta (Aβ), and insulin that play key roles in Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM), respectively. Crystal structure of IDE revealed that N-terminal of IDE has an exosite which serves as a regulation site by orientation of the substrates of IDE to the catalytic site. It is plausible to find small molecules that bind to the exosite of IDE and enhance its proteolytic activity towards different substrates. In this study, we have taken a computer-aided structure based drug design methods combined with experimental methods, one novel molecule that enhances the activity of human IDE was discovered. The novel compound, designated as D10 enhanced both IDE mediated proteolysis of substrate V and insulin degradation. This study describes the first examples of a computer-aided discovery of IDE regulators, showing that in vitro activation of this important enzyme with drug-like small molecules is attainable.