N-(4-Substituted-benzoyl)-N′-(β-d-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase: Synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods

Structure based inhibitor design targeting glycogen phosphorylase b. Virtual screening, synthesis, biochemical and biological assessment of novel N-acyl-β-d-glucopyranosylamines

“…Thus, it seems that the presence of the R group of the two inhibitors induces the between the phenyl rings of Phe285 and Tyr613, two residues that constitute the inhibitor site at the entrance of the catalytic site in GPb, resulting in its disruption. This rearrangement of the 280s loop is in the direction of the R to T allosteric conversion and has been also observed in other GPb ligand complexes with bulky benzoyl moieties [48][49][50] .…”

“…A structural comparison with the GPb -N-4-phenylbenzoyl-2-N'-β-D-glycopyranosyl urea complex 49 (PDB id: 2qln), the inhibitor (Ki=3.7 µM ) used as a scaffold for modelling reveals that S1 and S3 bind very similar with this compound. However, both S1 and S3 lack the second carbonyl oxygen in the linker of the scaffold compound and thus are not involved in any of the additional water-mediated of the scaffold compound and Gly134, Gly135, Gly137, and Asp283.…”

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

“…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.…”

“…17 Introduction of a methyl group in the 4-position of the phenyl ring as in 20 resulted in a weaker inhibition than that of 19, and this is again different from compounds E-G in which this modification (or 4-OMe substitution) gave more effective inhibitors. 17,22 This behaviour may reveal a rather unfavourable orientation of the aromatic part of these compounds in the active site β-pocket of the enzyme.…”

Synthesis, enzyme kinetics and computational evaluation of N-(β-d-glucopyranosyl) oxadiazolecarboxamides as glycogen phosphorylase inhibitors

“…13 Among them the glucose based inhibitors targeting the catalytic site are the most extensively investigated derivatives [14][15][16][17] and a glucopyranosylidene-spiro-thiohydantoin has been shown to have appreciable in vivo hypoglycaemic effects. and N-acyl-N 0 -b-D-glucopyranosyl ureas (II) 13,22,23 are among the best glucose analogue inhibitors of GP discovered to date, which 70 are efficient in or below the low micromolar range. Bioisosteric replacement is widely used in medicinal chemistry to design new drug molecules by systematic modification of lead compounds.…”