Identification of a small molecule that selectively inhibits mouse PC2 over mouse PC1/3: a computational and experimental study

PLoS One. 2013;8(2):e56957. doi: 10.1371/journal.pone.0056957. Epub 2013 Feb 22.

Abstract

The calcium-dependent serine endoproteases prohormone convertase 1/3 (PC1/3) and prohormone convertase 2 (PC2) play important roles in the homeostatic regulation of blood glucose levels, hence implicated in diabetes mellitus. Specifically, the absence of PC2 has been associated with chronic hypoglycemia. Since there is a reasonably good conservation of the catalytic domain between species translation of inhibitory effects is likely. In fact, similar results have been found using both mouse and human recombinant enzymes. Here, we employed computational structure-based approaches to screen 14,400 compounds from the Maybridge small molecule library towards mouse PC2. Our most remarkable finding was the identification of a potent and selective PC2 inhibitor. Kinetic data showed the compound to be an allosteric inhibitor. The compound identified is one of the few reported selective, small-molecule inhibitors of PC2. In addition, this new PC2 inhibitor is structurally different and of smaller size than those reported previously. This is advantageous for future studies where structural analogues can be built upon.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / pharmacology*
  • Mice
  • Proprotein Convertase 1 / antagonists & inhibitors*
  • Proprotein Convertase 2 / antagonists & inhibitors*
  • Proprotein Convertases / antagonists & inhibitors

Substances

  • Enzyme Inhibitors
  • Proprotein Convertases
  • Proprotein Convertase 1
  • Proprotein Convertase 2