New Inhibitors of Glycogen Phosphorylase as Potential Antidiabetic Agents

Abstract

The protein glycogen phosphorylase has been linked to type 2 diabetes, indicating the importance of this target to human health. Hence, the search for potent and selective inhibitors of this enzyme, which may lead to antihyperglycaemic drugs, has received particular attention. Glycogen phosphorylase is a typical allosteric protein with five different ligand binding sites, thus offering multiple opportunities for modulation of enzyme activity. The present survey is focused on recent new molecules, potential inhibitors of the enzyme. The biological activity can be modified by these molecules through direct binding, allosteric effects or other structural changes. Progress in our understanding of the mechanism of action of these inhibitors has been made by the determination of high-resolution enzyme inhibitor structures (both muscle and liver). The knowledge of the three-dimensional structures of protein-ligand complexes allows analysis of how the ligands interact with the target and has the potential to facilitate structure-based drug design. In this review, the synthesis, structure determination and computational studies of the most recent inhibitors of glycogen phosphorylase at the different binding sites are presented and analyzed.

Glucopyranosylidene-spiro-iminothiazolidinone, a new bicyclic ring system: Synthesis, derivatization, and evaluation for inhibition of glycogen phosphorylase by enzyme kinetic and crystallographic methods

“…As it was anticipated, the difference electron density maps (Figure 1, right) confirmed that compound 22 also binds at the catalytic site of the enzyme and the 2-naphthyl group is accommodated in the so-called β-subsite, in accordance with previous compounds with such a substituent. 2 A portion of additional electron density was observed at the new allosteric site of the enzyme that could be attributed to the 2-naphthyl group only. Previous studies have shown that glucose analogues bearing this group bound at both the catalytic and the new allosteric site.…”

“…17,22 In this series X-ray crystallography of the enzymeinhibitor complexes 2,23 indicated the absence of the above mentioned hydrogen bond between the β-NH group and His377 O; therefore, the stronger binding was attributed to extensive interactions with the large aromatic appendage of the inhibitor in the so-called β-channel of the protein. A variant of E with a 3,5-dimethyl-phenyl group in place of the 2-naphthyl moiety was shown to improve glucose tolerance and to rearrange hepatic metabolism in diabetic mice.…”

“…Inhibition of glycogen phosphorylase (GP), the main regulatory enzyme of glycogen metabolism, has been connected to type 2 diabetes mellitus, [2][3][4][5] and during the last decade also to other diseased states such as myocardial 6,7 and cerebral 8,9 ischemia as well as tumors [10][11][12][13] as amply discussed in recent reviews and primary research articles. Liver and muscle isoforms of GP have been thoroughly characterized, the structural features of the proteins and the binding sites are well known and have been surveyed, 14,15 therefore these enzymes are ideal targets for rational and structure-based inhibitor design.…”

“…Several structural classes of compounds for inhibition of GP have been designed and evaluated 2,5,16 (mostly with the prototype of GP 14 isolated from rabbit muscle (RMGPb)) among which the most populated group is that of the glucose analogues which bind mostly at the catalytic site. 14,15,17 The evolution of some glucose based compounds leading to the first low micromolar inhibitor of GP is exemplified in Chart 1 by compounds A-C.…”

4(5)-Aryl-2-C-glucopyranosyl-imidazoles as New Nanomolar Glucose Analogue Inhibitors of Glycogen Phosphorylase

“…9,10 GPIs comprise a very broad array of compounds with high structural diversity due to the peculiarities of several binding clefts (the catalytic, allosteric and new allosteric, inhibitor, glycogen storage, benzimidazole, and quercetin sites) discovered so far. 11,12 Several nanomolar inhibitors with various heterocyclic scaffolds, amply discussed in review articles, 11,12 bind to the allosteric or the new allosteric sites of GP. The most populated class of GPIs is represented by glucose derivatives, which bind primarily to the catalytic site of the enzyme showing competitive inhibition.…”