Begum, Jaida, Varga, Gergely, Docsa, Tibor, Gergely, Pál, Hayes, Joseph M., Juhász, László and Somsák, László (2015) Computationally motivated synthesis and enzyme kinetic evaluation of N-(β-d-glucopyranosyl)-1,2,4-triazolecarboxamides as glycogen phosphorylase inhibitors. Med. Chem. Commun., 6 (1). pp. 80-89. ISSN 2040-2503
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Official URL: http://dx.doi.org/10.1039/c4md00335g
Following our recent study of N-(β-D-glucopyranosyl)-oxadiazole-carboxamides (Polyák et al., Biorg. Med. Chem. 2013, 21, 5738) revealed as moderate inhibitors of glycogen phosphorylase (GP), in silico docking calculations using Glide have been performed on N-(β-D-glucopyranosyl)-1,2,4-triazolecarboxamides with different aryl substituents predicting more favorable binding at GP. The ligands were subsequently synthesized in moderate yields using N-(2,3,4,6-terta-O-acetyl-β-D-glucopyranosyl)-tetrazole-5-carboxamide as starting material. Kinetics experiments against rabbit muscle glycogen phosphorylase b (RMGPb) revealed the ligands to be low µM GP inhibitors; the phenyl analogue (Ki = 1 µM) is one of the most potent N-(β-D-glucopyranosyl)-heteroaryl-carboxamide-type inhibitors of the GP catalytic site discovered to date. Based on QM and QM/MM calculations, the potency of the ligands is predicted to arise from favorable intra- and intermolecular hydrogen bonds formed by the most stable solution phase tautomeric (t2) state of the 1,2,4-triazole in a conformationally dynamic system. ADMET property predictions revealed the compounds to have promising pharmacokinetic properties without any toxicity. This study highlights the benefits of a computationally lead approach to GP inhibitor design.
|Uncontrolled Keywords (separate with ;):||1,2,4-triazole; β-D-glucopyranosyl derivatives; glycogen phosphorylase; inhibitor; ADMET; docking; QM/MM|
|Subjects:||Physical sciences > Chemistry|
B - Subjects allied to medicine > B200 - Pharmacology, toxicology & pharmacy
|Schools:||Faculty of Science and Technology > School of Physical Sciences and Computing|
|Deposited By:||T Richard Hull|
|Deposited On:||24 Feb 2016 16:54|
|Last Modified:||27 Feb 2017 18:46|
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