6f3u
From Proteopedia
The crystal structure of Glycogen Phosphorylase in complex with 10h
Structural highlights
Function[PYGM_RABIT] Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. Publication Abstract from PubMed3-(beta-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<10muM (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-beta-d-glucopyranosyl tetrazole by N-benzyl-arenecarboximidoyl chlorides, ring closure of C-(beta-d-glucopyranosyl)formamidrazone with aroyl chlorides, or that of N-(beta-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 muM 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. A multidisciplinary study of 3-(beta-d-glucopyranosyl)-5-substituted-1,2,4-triazole derivatives as glycogen phosphorylase inhibitors: Computation, synthesis, crystallography and kinetics reveal new potent inhibitors.,Kun S, Begum J, Kyriakis E, Stamati ECV, Barkas TA, Szennyes E, Bokor E, Szabo KE, Stravodimos GA, Sipos A, Docsa T, Gergely P, Moffatt C, Patraskaki MS, Kokolaki MC, Gkerdi A, Skamnaki VT, Leonidas DD, Somsak L, Hayes JM Eur J Med Chem. 2018 Mar 10;147:266-278. doi: 10.1016/j.ejmech.2018.01.095. Epub , 2018 Feb 2. PMID:29453094[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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