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Lookup NU author(s): Dr Ziad Al-Oanzi, Professor Loranne Agius
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© 2019 American Chemical Society. Several C-β-d-glucopyranosyl azoles have recently been uncovered as among the most potent glycogen phosphorylase (GP) catalytic site inhibitors discovered to date. Toward further exploring their translational potential, ex vivo experiments have been performed for their effectiveness in reduction of glycogenolysis in hepatocytes. New compounds for these experiments were predicted in silico where, for the first time, effective ranking of GP catalytic site inhibitor potencies using the molecular mechanics-generalized Born surface area (MM-GBSA) method has been demonstrated. For a congeneric training set of 27 ligands, excellent statistics in terms of Pearson (RP) and Spearman (RS) correlations (both 0.98), predictive index (PI = 0.99), and area under the receiver operating characteristic curve (AU-ROC = 0.99) for predicted versus experimental binding affinities were obtained, with ligand tautomeric/ionization states additionally considered using density functional theory (DFT). Seven 2-aryl-4(5)-(β-d-glucopyranosyl)-imidazoles and 2-aryl-4-(β-d-glucopyranosyl)-thiazoles were subsequently synthesized, and kinetics experiments against rabbit muscle GPb revealed new potent inhibitors with best Ki values in the low micromolar range (5c = 1.97 μM; 13b = 4.58 μM). Ten C-β-d-glucopyranosyl azoles were then tested ex vivo in mouse primary hepatocytes. Four of these (5a-c and 9d) demonstrated significant reduction of glucagon stimulated glycogenolysis (IC50 = 30-60 μM). Structural and predicted physicochemical properties associated with their effectiveness were analyzed with permeability related parameters identified as crucial factors. The most effective ligand series 5 contained an imidazole ring, and the calculated pKa (Epik: 6.2; Jaguar 5.5) for protonated imidazole suggests that cellular permeation through the neutral state is favored, while within the cell, there is predicted more favorable binding to GP in the protonated form.
Author(s): Barr D, Szennyes E, Bokor E, Al-Oanzi ZH, Moffatt C, Kun S, Docsa T, Sipos A, Davies MP, Mathomes RT, Snape TJ, Agius L, Somsak L, Hayes JM
Publication type: Article
Publication status: Published
Journal: ACS Chemical Biology
Year: 2019
Volume: 14
Issue: 7
Pages: 1460-1470
Print publication date: 19/07/2019
Online publication date: 03/06/2019
Acceptance date: 03/06/2019
ISSN (print): 1554-8929
ISSN (electronic): 1554-8937
Publisher: American Chemical Society
URL: https://doi.org/10.1021/acschembio.9b00172
DOI: 10.1021/acschembio.9b00172
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