6QA6

Glycogen Phosphorylase b in complex with 30

Summary for 6QA6

• Entry DOI: 10.2210/pdb6qa6/pdb
• Descriptor: Glycogen phosphorylase, muscle form, DIMETHYL SULFOXIDE, (5~{S},7~{R},8~{S},9~{S},10~{R})-7-(hydroxymethyl)-2-naphthalen-2-yl-8,9,10-tris(oxidanyl)-6-oxa-1,3-diazaspiro[4.5]dec-1-en-4-one, ... (5 entities in total)
• Functional Keywords: transferase
• Biological source: Oryctolagus cuniculus (Rabbit)
• Total number of polymer chains: 1
• Total formula weight: 98464.36

Authors

Kyriakis, E.,Stravodimos, G.A.,Skamnaki, V.T.,Leonidas, D.D. (deposition date: 2018-12-18, release date: 2019-06-26, Last modification date: 2019-07-24)

Primary citation

Szabo, K.E.,Kyriakis, E.,Psarra, A.G.,Karra, A.G.,Sipos, A.,Docsa, T.,Stravodimos, G.A.,Katsidou, E.,Skamnaki, V.T.,Liggri, P.G.V.,Zographos, S.E.,Mandi, A.,Kiraly, S.B.,Kurtan, T.,Leonidas, D.D.,Somsak, L.
Glucopyranosylidene-spiro-imidazolinones, a New Ring System: Synthesis and Evaluation as Glycogen Phosphorylase Inhibitors by Enzyme Kinetics and X-ray Crystallography.
J.Med.Chem., 62:6116-6136, 2019

PubMed Abstract: Epimeric series of aryl-substituted glucopyranosylidene-spiro-imidazolinones, an unprecedented new ring system, were synthesized from the corresponding Schiff bases of -perbenzoylated (gluculopyranosylamine)onamides by intramolecular ring closure of the aldimine moieties with the carboxamide group elicited by -bromosuccinimide in pyridine. Test compounds were obtained by Zemplén -debenzoylation. Stereochemistry and ring tautomers of the new compounds were investigated by NMR, time-dependent density functional theory (TDDFT)-electronic circular dichroism, and DFT-NMR methods. Kinetic studies with rabbit muscle and human liver glycogen phosphorylases showed that the ()-imidazolinones were 14-216 times more potent than the () epimers. The 2-naphthyl-substituted ()-imidazolinone was the best inhibitor of the human enzyme ( 1.7 μM) and also acted on HepG2 cells (IC 177 μM). X-ray crystallography revealed that only the () epimers bound in the crystal. Their inhibitory efficacy is based on the hydrogen-bonding interactions of the carbonyl oxygen and the NH of the imidazolinone ring.

PubMed: 31251604
DOI: 10.1021/acs.jmedchem.9b00356

Experimental method

X-RAY DIFFRACTION (2.4 Å)