title: Identification of a small molecule that selectively inhibits mouse PC2 over mouse PC1/3: a computational and experimental study.
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.
authors: Torrey Pines Institute for Molecular Studies, Port St Lucie, Florida, United States of America.
authors: Austin B
authors: AB
authors: Yongye
authors: Mirella
authors: M
authors: Vivoli
authors: Iris
authors: I
authors: Lindberg
authors: Jon R
authors: JR
authors: Appel
authors: Richard A
authors: RA
authors: Houghten
authors: Karina
authors: K
authors: Martinez-Mayorga
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D045664:Proprotein Convertase 1 / Q000037:antagonists & inhibitors*; D045706:Proprotein Convertase 2 / Q000037:antagonists & inhibitors*; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; D043484:Proprotein Convertases; D045664:Proprotein Convertase 1; D045706:Proprotein Convertase 2