Dipeptidyl Peptidase-IV Blockers Potently Inhibit Monoglyceride Lipase: Investigation By Docking Studies And In Vitro Bioassay

Monoglyceride lipase (MGL) is an important enzyme that plays a critical role in lipolysis and release of free fatty acids from triacylglycerides stores. High levels of circulating free fatty acids impair insulin sensitivity and induce inflammation. Several studies have shown that dipeptidyl peptidase-IV (DPP-IV) inhibitors can improve insulin sensitivity and suppress inflammatory response by unknown mechanism. Structural similarities between DPP-IV and MGL prompted us to propose that DPP-IV inhibitors can block MGL. Accordingly, we evaluated 6 known DPP-IV inhibitors as potential MGL blockers using docking experiments and in vitro bioassay. All tested compounds were successfully docked into the catalytic site of MGL. Vildagliptin, sitagliptin, omarigliptin and trelagliptin illustrated significant anti-MGL inhibitory percentages at 10 mu M, while gosogliptin and saxagliptin were rather potent MGL inhibitors with IC50 values of 6.9 nM and 136.2 nM, respectively. This is the first time to report potent inhibitory effects of DPP-IV inhibitors against MGL. This finding provide evidence for a new mechanism by which DPP-IV inhibitors improve insulin sensitivity and suppress inflammation response independent of incretin hormones pathway.

Automated summary

Monoglyceride lipase (MGL) is a critical enzyme in lipolysis and the release of free fatty acids, and its inhibition by dipeptidyl peptidase-IV (DPP-IV) inhibitors provides a novel mechanism for improving insulin sensitivity and suppressing inflammation response. In this study, 6 known DPP-IV inhibitors were evaluated as potential MGL blockers, and all compounds showed successful docking into the catalytic site of MGL. Some of the inhibitors exhibited significant anti-MGL inhibitory effects, with gosogliptin and saxagliptin being the most potent inhibitors. This finding suggests a new therapeutic target for DPP-IV inhibitors beyond their traditional role in incretin hormones pathway.