Computational Design of Inhibitors of the Glycogenolysis Pathway as Potential Treatment for Type II Diabetes
Separate studies for type 1 diabetes (Diabetes Control & Complication Trial, 1993) and for type 2 diabetes (UK Prospective Diabetes Study, 1998) have concluded that the longer term complications of diabetes such as cardiovascular diseases, neuropathies, nephropathies, retinopathies or hypertension could be prevented if blood glucose levels can be controlled. Current pharmacological therapies for type 2 diabetes have limited efficacy in this regard, while the sometimes severe side-effects also associated with these medications necessitate the need for new and safer drugs.
Phosphorylase kinase(PhK) and glycogen phosphorylase (GP) have a direct effect on blood glucose levels via the glycogenolysis pathway. By regulating their activity, therefore, one has the potential to control glucose levels in type 2 diabetic patients. This project focusses on the computational design of new and better inhibitors of PhK and GP, with the predictions validated experimentally in a multidisciplinary approach to drug design. The experimental work (synthesis, X-ray crystallography and biochemical assessment) involves a number of collaborations throughout Europe.
Project Lead: Dr. Joseph M. Hayes
Collaborators and Partners
Prof. Demetres Leonidas, University of Thessaly, Larissa, Greece
Prof. Laslo Somsak, University of Debrecen, Hungary
Dr. Vicky Skamnaki, University of Thessaly, Larissa, Greece
Dr. Spyros Zographos, National Hellenic Research Foundation, Athens, Greece
Clients or Funders
Commission of the European Communities, under the FP7 “SP4-Capacities Coordination and Support Action, Support Actions” EUROSTRUCT project (CSA-SA_FP7-REGPOT-2008-1 Grant Agreement No. 230146); 1,008,989€ (2009-2012)
DRUGDESI: Marie Curie Host Fellowships for the Transfer of Knowledge (ToK) contract no MTKD-CT-2006-042776; 186,396€ (2007-2011)
Peer Reviewed Publications
- Polyak M, Varga G, Szilagyi B, Juhász L*, Docsa T, Gergely P, Begum J, Hayes JM, Somsak L*, “Synthesis, enzyme kinetics and computational evaluation of N-(β-D-glucopyranosyl) oxadiazolecarboxamides as glycogen phosphorylase inhibitors”, Biorg. Med. Chem. (2013), in press.
- Tsitsanou KE, Hayes JM*, Keramioti M, Mamais M, Oikonomakos NG, Kato A, Leonidas DD, Zographos SE, “Sourcing the affinity of flavanoids for the glycogen phosphorylase inhibitor site via crystallography, kinetics and QM/MM-PBSA binding studies: Comparison of chrysin and flavopiridol”, Food & Chem. Tox. (2013), in press (http://dx.doi.org/10.1016/j.fct.2012.12.030)
- Kantsadi AL, Hayes JM*, Manta S, Skamnaki VT, Kiritsis C, Psarra A-MG, Koutsogiannis Z, Dimopoulou A, Theofanous S, Nikoleousakos N, Zoumpoulakis P, Kontou M, Papadopoulos G, Zographos SE, Komiotis D*, Leonidas DD*, “The sigma-hole phenomenon of halogen atoms forms the structural basis of the strong inhibitory potency of C5 halogen substituted glucopyranosyl nucleosides towards glycogen phosphorylase b”, ChemMedChem (2012), 7, 722-732.
- Manta S, Xipnitou A, Kiritsis C, Kantsadi AL, Hayes JM*, Skamnaki VT, Lamprakis C, Kontou M, Zoumpoulakis P, Zographos SE, Leonidas DD*, Komiotis D*, “3’-axial CH2OH substitution on glucopyranose does not increase glycogen phosphorylase inhibitory potency. QM/MM-PBSA calculations suggest why.”, Chem. Biol. Drug Des. (2012), 79, 663-673.
Hayes JM*, Skamnaki VT, Archontis G, Lamprakis C, Sarrou J, Bischler N, Skaltsounis A-L, Zographos SE, Oikonomakos NG, “Kinetics, in silico docking, molecular dynamics and MM-GBSA binding studies on prototype indirubins, KT5720 and staurosporine as phosphorylase kinase ATP-binding site inhibitors: the role of water molecules examined”, Proteins: Structure, Function & Bioinformatics (2011), 79, 703-719.
Hayes JM*, Leonidas DD, “Computation as a tool for glycogen phosphorylase inhibitor design”, Mini. Rev. Med. Chem. (2010), 10, 1156-1174.
Tsirkone VG, Tsoukala E, Lamprakis C, Manta S, Hayes JM, Skamnaki VT, Drakou C, Zographos SE, Komiotis D, Leonidas DD*, “1-(3-Deoxy-3-fluoro-beta-D-glucopyranosyl) pyrimidine derivatives as inhibitors of glycogen phosphorylase b: Kinetic, crystallographic and modeling studies”, Biorg. Med. Chem. (2010), 18, 3413-3425.
Benltifa M, Hayes JM, Vidal S, Gueyrard D, Goekjian PG, Praly JP,* Kizilis G, Tiraidis C, Alexacou K-M, Chrysina ED*, Zographos SE, Leonidas DD, Archontis G, and Oikonomakos NG, “Glucose-based Spiro-isoxazolines: A New Family of Potent Glycogen Phosphorylase Inhibitors”, Biorg. Med. Chem. (2009), 17, 7368-7380.
Somsák L*, Czifrák K, Tóth M, Bokor E, Chrysina ED, Alexacou K-M, Hayes JM, Lazoura E, Leonidas DD, Zographos SE, Oikonomakos NG*. “New Inhibitors of Glycogen Phosphorylase as Potential Antidiabetic Agents”, Current Medicinal Chemistry (2008), 15, 2933-2983.
Wen X, Sun H, Liu J, Cheng K, Zhang P, Zhang L, Hao J, Zhang L, Ni P, Zographos SE, Leonidas DD, Alexacou KM, Gimisis T, Hayes JM, Oikonomakos NG*. “Naturally Occurring Pentacyclic Triterpenes as Inhibitors of Glycogen Phosphorylase: Synthesis, Structure-Activity Relationships and X-ray Crystallographic Studies”, J. Med. Chem. (2008), 51, 3540-3544.
Alexacou KM, Hayes JM, Tiraidis C, Zographos SE, Leonidas DD, Chrysina ED, Archontis G, Oikonomakos NG*, Paul JV, Varghese B, Loganathan D*, “Crystallographic and computational studies on 4-phenyl-N-(b-D-glucopyranosyl)-1H-1,2,3-triazole-1-acetamide, an inhibitor of glycogen phosphorylase: Comparison with a-D-glucose, N-acetyl-b-D-glucopyranosylamine and N-benzoyl-N0-b-D-glucopyranosyl urea binding”, Proteins: Structure, Function & Bioinformatics (2008), 71, 301-307.
Papers and symposia related to the above work presented at various international conferences.