Pentacyclic triterpenes, inhibitors of glycogen phosphorylase, as potential drugs for type 2 diabetes: X-ray crystallographic studies

Abstract

Twenty-five naturally occurring pentacyclic tritepenes were identified as inhibitors for muscle glycogen phosphorylase a (GPa), a molecular target to control hyperglycaemia in type 2 diabetes. To elucidate the mechanism of inhibition for these compounds, the crystal structures of the GPb-asiatic acid and GPb-maslinic acid complexes were performed and refined to 2.4 Å, and 2.7 Å resolution, respectively [1]. The structures demonstrated that the inhibitors bind at the allosteric activator site. The position of the inhibitors was partially overlapping, with the position of the physiological activator AMP bound to the R-state of the human liver enzyme. The contacts from the inhibitors to RMGPb are dominated by ionic interactions from the carboxylate group to the Arg310 of the allosteric phosphate-subsite, and also by nonpolar van der Waals interactions to Tyr75, Phe196, and Val45' (from the symmetry related subunit). These interactions appear important in stabilizing the inactive quaternary T-state of the enzyme. The structural analyses of these compounds can be further exploited towards the development of better inhibitors.