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The binding of β-d-glucopyranosyl-thiosemicarbazone derivatives to glycogen phosphorylase: A new class of inhibitors.

Alexacou KM, Tenchiu Deleanu AC, Chrysina ED, Charavgi MD, Kostas ID, Zographos SE, Oikonomakos NG, Leonidas DD
Bioorg Med Chem 18 7911-22 (2010)
Related entries: 3mqf, 3mrt, 3mrv, 3mrx, 3ms4, 3ms7, 3msc, 3mt7, 3mt8, 3mt9, 3mta, 3mtb, 3mtd, 3nc4

Cited: 14 times
EuropePMC logo PMID: 20947361

Abstract

Glycogen phosphorylase (GP) is a promising target for the treatment of type 2 diabetes. In the process of structure based drug design for GP, a group of 15 aromatic aldehyde 4-(β-d-glucopyranosyl)thiosemicarbazones have been synthesized and evaluated as inhibitors of rabbit muscle glycogen phosphorylase b (GPb) by kinetic studies. These compounds are competitive inhibitors of GPb with respect to α-d-glucose-1-phosphate with IC(50) values ranging from 5.7 to 524.3μM. In order to elucidate the structural basis of their inhibition, the crystal structures of these compounds in complex with GPb at 1.95-2.23Å resolution were determined. The complex structures reveal that the inhibitors are accommodated at the catalytic site with the glucopyranosyl moiety at approximately the same position as α-d-glucose and stabilize the T conformation of the 280s loop. The thiosemicarbazone part of the studied glucosyl thiosemicarbazones possess a moiety derived from substituted benzaldehydes with NO(2), F, Cl, Br, OH, OMe, CF(3), or Me at the ortho-, meta- or para-position of the aromatic ring as well as a moiety derived from 4-pyridinecarboxaldehyde. These fit tightly into the β-pocket, a side channel from the catalytic site with no access to the bulk solvent. The differences in their inhibitory potency can be interpreted in terms of variations in the interactions of the aldehyde-derived moiety with protein residues in the β-pocket. In addition, 14 out of the 15 studied inhibitors were found bound at the new allosteric site of the enzyme.

Reviews citing this publication (1)

  1. Glycogen phosphorylase inhibitors: a patent review (2008 - 2012). Gaboriaud-Kolar N, Skaltsounis AL. Expert Opin Ther Pat 23 1017-1032 (2013)

Articles citing this publication (13)

  1. Natural flavonoids as antidiabetic agents. The binding of gallic and ellagic acids to glycogen phosphorylase b. Kyriakis E, Stravodimos GA, Kantsadi AL, Chatzileontiadou DS, Skamnaki VT, Leonidas DD. FEBS Lett 589 1787-1794 (2015)
  2. Synthetic, enzyme kinetic, and protein crystallographic studies of C-β-d-glucopyranosyl pyrroles and imidazoles reveal and explain low nanomolar inhibition of human liver glycogen phosphorylase. Kantsadi AL, Bokor É, Kun S, Stravodimos GA, Chatzileontiadou DSM, Leonidas DD, Juhász-Tóth É, Szakács A, Batta G, Docsa T, Gergely P, Somsák L. Eur J Med Chem 123 737-745 (2016)
  3. The binding of C5-alkynyl and alkylfurano[2,3-d]pyrimidine glucopyranonucleosides to glycogen phosphorylase b: synthesis, biochemical and biological assessment. Kantsadi AL, Manta S, Psarra AM, Dimopoulou A, Kiritsis C, Parmenopoulou V, Skamnaki VT, Zoumpoulakis P, Zographos SE, Leonidas DD, Komiotis D. Eur J Med Chem 54 740-749 (2012)
  4. The σ-hole phenomenon of halogen atoms forms the structural basis of the strong inhibitory potency of C5 halogen substituted glucopyranosyl nucleosides towards glycogen phosphorylase b. Kantsadi AL, Hayes JM, Manta S, Skamnaki VT, Kiritsis C, Psarra AM, Koutsogiannis Z, Dimopoulou A, Theofanous S, Nikoleousakos N, Zoumpoulakis P, Kontou M, Papadopoulos G, Zographos SE, Komiotis D, Leonidas DD. ChemMedChem 7 722-732 (2012)
  5. Mechanistic Insights into Biological Activities of Polyphenolic Compounds from Rosemary Obtained by Inverse Molecular Docking. Lešnik S, Bren U. Foods 11 67 (2021)
  6. Structure based inhibitor design targeting glycogen phosphorylase B. Virtual screening, synthesis, biochemical and biological assessment of novel N-acyl-β-d-glucopyranosylamines. Parmenopoulou V, Kantsadi AL, Tsirkone VG, Chatzileontiadou DS, Manta S, Zographos SE, Molfeta C, Archontis G, Agius L, Hayes JM, Leonidas DD, Komiotis D. Bioorg Med Chem 22 4810-4825 (2014)
  7. Synthesis, enzyme kinetics and computational evaluation of N-(β-D-glucopyranosyl) oxadiazolecarboxamides as glycogen phosphorylase inhibitors. Polyák M, Varga G, Szilágyi B, Juhász L, Docsa T, Gergely P, Begum J, Hayes JM, Somsák L. Bioorg Med Chem 21 5738-5747 (2013)
  8. van der Waals interactions govern C-β-d-glucopyranosyl triazoles' nM inhibitory potency in human liver glycogen phosphorylase. Kantsadi AL, Stravodimos GA, Kyriakis E, Chatzileontiadou DSM, Solovou TGA, Kun S, Bokor É, Somsák L, Leonidas DD. J Struct Biol 199 57-67 (2017)
  9. A new synthetic access to 2-N-(glycosyl)thiosemicarbazides from 3-N-(glycosyl)oxadiazolinethiones and the regioselectivity of the glycosylation of their oxadiazolinethione precursors. El Ashry el SH, El Tamany el SH, Fattah Mel D, Aly MR, Boraei AT, Duerkop A. Beilstein J Org Chem 9 135-146 (2013)
  10. Synthesis of 2-(β-D-glucopyranosylamino)-5-substituted-1,3,4-oxadiazoles for inhibition of glycogen phosphorylase. Tóth M, Szőcs B, Kaszás T, Docsa T, Gergely P, Somsák L. Carbohydr Res 381 196-204 (2013)
  11. Pyrazole Incorporated New Thiosemicarbazones: Design, Synthesis and Investigation of DPP-4 Inhibitory Effects. Sever B, Soybir H, Görgülü Ş, Cantürk Z, Altıntop MD. Molecules 25 E5003 (2020)
  12. Outliers in SAR and QSAR: 4. effects of allosteric protein-ligand interactions on the classical quantitative structure-activity relationships. Kim KH. Mol Divers 26 3057-3092 (2022)
  13. Synthesis and antibacterial and antifungal activities of N-(tetra-O-acetyl-β-d-glucopyranosyl)thiosemicarbazones of substituted 4-formylsydnones. Thanh ND, Duc HT, Duyen VT, Tuong PM, Van Quoc N. Chem Cent J 9 60 (2015)


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