dc.creator | Kun S., Begum J., Kyriakis E., Stamati E.C.V., Barkas T.A., Szennyes E., Bokor É., Szabó K.E., Stravodimos G.A., Sipos Á., Docsa T., Gergely P., Moffatt C., Patraskaki M.S., Kokolaki M.C., Gkerdi A., Skamnaki V.T., Leonidas D.D., Somsák L., Hayes J.M. | en |
dc.date.accessioned | 2023-01-31T08:47:25Z | |
dc.date.available | 2023-01-31T08:47:25Z | |
dc.date.issued | 2018 | |
dc.identifier | 10.1016/j.ejmech.2018.01.095 | |
dc.identifier.issn | 02235234 | |
dc.identifier.uri | http://hdl.handle.net/11615/75546 | |
dc.description.abstract | 3-(β-D-Glucopyranosyl)-5-substituted-1,2,4-triazoles have been revealed as an effective scaffold for the development of potent glycogen phosphorylase (GP) inhibitors but with the potency very sensitive to the nature of the alkyl/aryl 5-substituent (Kun et al., Eur. J. Med. Chem. 2014, 76, 567). For a training set of these ligands, quantum mechanics-polarized ligand docking (QM-PLD) demonstrated good potential to identify larger differences in potencies (predictive index PI = 0.82) and potent inhibitors with Ki's < 10 μM (AU-ROC = 0.86). Accordingly, in silico screening of 2335 new analogues exploiting the ZINC docking database was performed and nine predicted candidates selected for synthesis. The compounds were prepared in O-perbenzoylated forms by either ring transformation of 5-β-D-glucopyranosyl tetrazole by N-benzyl-arenecarboximidoyl chlorides, ring closure of C-(β-D-glucopyranosyl)formamidrazone with aroyl chlorides, or that of N-(β-D-glucopyranosylcarbonyl)arenethiocarboxamides by hydrazine, followed by deprotections. Kinetics experiments against rabbit muscle GPb (rmGPb) and human liver GPa (hlGPa) revealed five compounds as potent low μM inhibitors with three of these on the submicromolar range for rmGPa. X-ray crystallographic analysis sourced the potency to a combination of favorable interactions from the 1,2,4-triazole and suitable aryl substituents in the GP catalytic site. The compounds also revealed promising calculated pharmacokinetic profiles. © 2018 Elsevier Masson SAS | en |
dc.language.iso | en | en |
dc.source | European Journal of Medicinal Chemistry | en |
dc.source.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85042026889&doi=10.1016%2fj.ejmech.2018.01.095&partnerID=40&md5=a717d87f6b8bb1e467629bf5b6fdd15d | |
dc.subject | 1,2,4 triazole derivative | en |
dc.subject | chloride | en |
dc.subject | glycogen phosphorylase | en |
dc.subject | glycogen phosphorylase inhibitor | en |
dc.subject | hydrazine | en |
dc.subject | transferase inhibitor | en |
dc.subject | unclassified drug | en |
dc.subject | 1,2,4-triazole | en |
dc.subject | enzyme inhibitor | en |
dc.subject | glycogen phosphorylase | en |
dc.subject | ligand | en |
dc.subject | triazole derivative | en |
dc.subject | Article | en |
dc.subject | chemical reaction kinetics | en |
dc.subject | computer model | en |
dc.subject | controlled study | en |
dc.subject | crystal structure | en |
dc.subject | data base | en |
dc.subject | deprotection reaction | en |
dc.subject | drug potency | en |
dc.subject | drug screening | en |
dc.subject | drug structure | en |
dc.subject | drug synthesis | en |
dc.subject | enzyme kinetics | en |
dc.subject | human | en |
dc.subject | hydrogen bond | en |
dc.subject | Leporidae | en |
dc.subject | liver | en |
dc.subject | molecular docking | en |
dc.subject | nonhuman | en |
dc.subject | quantum mechanics | en |
dc.subject | X ray crystallography | en |
dc.subject | antagonists and inhibitors | en |
dc.subject | Caco-2 cell line | en |
dc.subject | chemical structure | en |
dc.subject | chemistry | en |
dc.subject | dose response | en |
dc.subject | kinetics | en |
dc.subject | metabolism | en |
dc.subject | molecular model | en |
dc.subject | quantum theory | en |
dc.subject | structure activity relation | en |
dc.subject | synthesis | en |
dc.subject | X ray crystallography | en |
dc.subject | Caco-2 Cells | en |
dc.subject | Crystallography, X-Ray | en |
dc.subject | Dose-Response Relationship, Drug | en |
dc.subject | Enzyme Inhibitors | en |
dc.subject | Glycogen Phosphorylase | en |
dc.subject | Humans | en |
dc.subject | Kinetics | en |
dc.subject | Ligands | en |
dc.subject | Models, Molecular | en |
dc.subject | Molecular Structure | en |
dc.subject | Quantum Theory | en |
dc.subject | Structure-Activity Relationship | en |
dc.subject | Triazoles | en |
dc.subject | Elsevier Masson SAS | en |
dc.title | A multidisciplinary study of 3-(β-D-glucopyranosyl)-5-substituted-1,2,4-triazole derivatives as glycogen phosphorylase inhibitors: Computation, synthesis, crystallography and kinetics reveal new potent inhibitors | en |
dc.type | journalArticle | en |