Structure based discovery of small molecules to regulate the activity of insulin degrading enzyme

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 is ∼30 Å away from the catalytic region and serves as a regulation site by orientation of the substrates of IDE to the catalytic site. In this study, we applied structure based drug design methodology to discover novel small molecule organic compounds that enhance the activity of human IDE. The activity of novel compounds were tested using in vitro essays by enhanced IDE mediated proteolysis of substrate V, insulin and FAβB degradation, respectively. These compounds demonstrated submicromolar activation. In addition, amino acid mutations at the exosite of IDE verifies that the designed molecules bind to the targeted area. This study describes the first examples of a computer-aided discovery of IDE regulators, showing that in vitro activation of this important enzyme with small molecules is possible.