6F3S

The crystal structure of Glycogen Phosphorylase in complex with 10d

Summary for 6F3S

• Entry DOI: 10.2210/pdb6f3s/pdb
• Descriptor: Glycogen phosphorylase, muscle form, PYRIDOXAL-5'-PHOSPHATE, (2~{R},3~{S},4~{R},5~{R},6~{S})-2-(hydroxymethyl)-6-[5-(4-phenylphenyl)-4~{H}-1,2,4-triazol-3-yl]oxane-3,4,5-triol, ... (4 entities in total)
• Functional Keywords: transferase
• Biological source: Oryctolagus cuniculus (Rabbit)
• Total number of polymer chains: 1
• Total formula weight: 98052.94

Authors

Kyriakis, E.,Stamati, E.C.V.,Stravodimos, G.A.,Skamnaki, V.T.,Leonidas, D.D. (deposition date: 2017-11-28, release date: 2018-02-28)

Primary citation

Kun, S.,Begum, J.,Kyriakis, E.,Stamati, E.C.V.,Barkas, T.A.,Szennyes, E.,Bokor, E.,Szabo, K.E.,Stravodimos, G.A.,Sipos, A.,Docsa, T.,Gergely, P.,Moffatt, C.,Patraskaki, M.S.,Kokolaki, M.C.,Gkerdi, A.,Skamnaki, V.T.,Leonidas, D.D.,Somsak, L.,Hayes, J.M.
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.
Eur J Med Chem, 147:266-278, 2018

PubMed 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 K'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.

PubMed: 29453094
DOI: 10.1016/j.ejmech.2018.01.095

Experimental method

X-RAY DIFFRACTION (1.9 Å)