Crystallographic studies on N-azidoacetyl-β-d-glucopyranosylamine, an inhibitor of glycogen phosphorylase: Comparison with N-acetyl-β-d-glucopyranosylamine

Petsalaki, Evangelia; Chrysina, Evangelia D.; Tiraidis, C.; Hadjiloi, Theodoros; Leonidas, D.D.; Oikonomakos, Nikos G.; Aich, Udayanath; Varghese, Babu; Loganathan, Duraikkannu

doi:10.1016/j.bmc.2006.03.044

Cited by 9 publications

(4 citation statements)

References 32 publications

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“…The mode of binding and the interactions that glucosyltriazolylacetamide makes with GPb, are similar to those described previously for the lead molecule in the 1.9 Å resolution structure of the GPb‐NAG complex 9. The hydrogen bond of the amide nitrogen (N1) with His377 O is retained, an interaction that is conserved in all β‐ D ‐glucopyranosylamine analogues,10, 16, 52–54 spirohydantoin analogues, and spirodiketopiperazine of β‐ D ‐glucopyranose,20, 51, 54–59 and also the compound 2‐(β‐ D ‐glucopyranosyl)‐benzimidazole 60. O7 is hydrogen‐bonded to Glu88 OE2, and residues of the glycine helix (residues 134–150), Gly134 N, and Gly137 through four water molecules (Wat268, Wat43, Wat415, Wat670) (SM Table V).…”

Section: Resultssupporting

confidence: 72%

Crystallographic and computational studies on 4‐phenyl‐N‐(β‐D‐glucopyranosyl)‐1H‐1,2,3‐triazole‐1‐acetamide, an inhibitor of glycogen phosphorylase: Comparison with α‐D‐glucose, N‐acetyl‐β‐D‐glucopyranosylamine and N‐benzoyl‐N′‐β‐D‐glucopyranosyl urea binding

et al. 2007

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4-Phenyl-N-(beta-D-glucopyranosyl)-1H-1,2,3-triazole-1-acetamide (glucosyltriazolylacetamide) has been studied in kinetic and crystallographic experiments with glycogen phosphorylase b (GPb), in an effort to utilize its potential as a lead for the design of potent antihyperglycaemic agents. Docking and molecular dynamics (MD) calculations have been used to monitor more closely the binding modes in operation and compare the results with experiment. Kinetic experiments in the direction of glycogen synthesis showed that glucosyltriazolylacetamide is a better inhibitor (K(i) = 0.18 mM) than the parent compound alpha-D-glucose (K(i) = 1.7 mM) or beta-D-glucose (K(i) = 7.4 mM) but less potent inhibitor than the lead compound N-acetyl-beta-D-glucopyranosylamine (K(i) = 32 microM). To elucidate the molecular basis underlying the inhibition of the newly identified compound, we determined the structure of GPb in complex with glucosyltriazolylacetamide at 100 K to 1.88 A resolution, and the structure of the compound in the free form. Glucosyltriazolylacetamide is accommodated in the catalytic site of the enzyme and the glucopyranose interacts in a manner similar to that observed in the GPb-alpha-D-glucose complex, while the substituent group in the beta-position of the C1 atom makes additional hydrogen bonding and van der Waals interactions to the protein. A bifurcated donor type hydrogen bonding involving O3H, N3, and N4 is seen as an important structural motif strengthening the binding of glucosyltriazolylacetamide with GP which necessitated change in the torsion about C8-N2 bond by about 62 degrees going from its free to the complex form with GPb. On binding to GP, glucosyltriazolylacetamide induces significant conformational changes in the vicinity of this site. Specifically, the 280s loop (residues 282-288) shifts 0.7 to 3.1 A (CA atoms) to accommodate glucosyltriazolylacetamide. These conformational changes do not lead to increased contacts between the inhibitor and the protein that would improve ligand binding compared with the lead compound. In the molecular modeling calculations, the GOLD docking runs with and without the crystallographic ordered cavity waters using the GoldScore scoring function, and without cavity waters using the ChemScore scoring function successfully reproduced the crystallographic binding conformation. However, the GLIDE docking calculations both with (GLIDE XP) and without (GLIDE SP and XP) the cavity water molecules were, impressively, further able to accurately reproduce the finer details of the GPb-glucosyltriazolylacetamide complex structure. The importance of cavity waters in flexible receptor MD calculations compared to "rigid" (docking) is analyzed and highlighted, while in the MD itself very little conformational flexibility of the glucosyltriazolylacetamide ligand was observed over the time scale of the simulations.

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Section: Resultssupporting

confidence: 72%

Crystallographic and computational studies on 4‐phenyl‐N‐(β‐D‐glucopyranosyl)‐1H‐1,2,3‐triazole‐1‐acetamide, an inhibitor of glycogen phosphorylase: Comparison with α‐D‐glucose, N‐acetyl‐β‐D‐glucopyranosylamine and N‐benzoyl‐N′‐β‐D‐glucopyranosyl urea binding

et al. 2007

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“…Uncited references [21-26,] [29][30][31][32][33][34][35][36][37], [48][49][50][51], [54,55,58], [74,78]. …”

Section: Note Added In Proofmentioning

confidence: 99%

Glucose derived inhibitors of glycogen phosphorylase

Somsák

2010

Comptes Rendus. Chimie

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“…G O 3.1 28,29 4.2 26,30 H S 5.1 26,30 [lM]) for some representative inhibitors of rabbit muscle glycogen phosphorylase. 24,25,27…”

Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

Glucose-based spiro-heterocycles as potent inhibitors of glycogen phosphorylase

Nagy

Benltifa

Vidal

et al. 2009

Bioorganic & Medicinal Chemistry

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Glucopyranosylidene-spiro-1,4,2-oxathiazoles were prepared in high yields by NBS-mediated spiro-cyclization of the corresponding glucosyl-hydroximothioates. In an effort to synthesize analogous glucopyranosylidene-spiro-1,2,4-oxadiazolines, with a nitrogen atom instead of the sulphur, attempted cyclizations resulted in aromatization of the heterocycle with opening of the pyranosyl ring. Enzymatic measurements showed that some of the glucose-based inhibitors were active in the micromolar range. The 2-naphthyl-substituted 1,4,2-oxathiazole displayed the best inhibition against RMGPb (K(i)=160 nM), among glucose-based inhibitors known to date.

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Crystallographic studies on N-azidoacetyl-β-d-glucopyranosylamine, an inhibitor of glycogen phosphorylase: Comparison with N-acetyl-β-d-glucopyranosylamine

Cited by 9 publications

References 32 publications

Glucose derived inhibitors of glycogen phosphorylase

Glucose-based spiro-heterocycles as potent inhibitors of glycogen phosphorylase

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