Τόμος 13 (1999) – Τεύχος 1 – Άρθρο 2 – Επιθεώρηση Κλινικής Φαρμακολογίας και Φαρμακοκινητικής-Διεθνής Έκδοση – Volume 13 (1999) – Issue 1 – Article 2 – Epitheorese Klinikes Farmakologias και Farmakokinetikes-International Edition

Title Molecular recognition in glycogen phosphorylase inhibitor design
Authors Katerina E. Tsitsanou, Spyros E. Zographos, Vicky T. Skamnaki and Nikos G. Oikonomakos

Institute of Biological Research and Biotechnology, The National Hellenic Research Foundation, 48 Vas. Constantinou Avenue, 116 35 Athens, Greece

Citation Tsitsanou, K.E., Zographos, S.E., Skamnaki, V.T., Oikonomakos, N.G.: Molecular recognition in glycogen phosphorylase inhibitor design, Epitheorese Klin. Farmakol. Farmakokinet. 13(1): 9-25 (1999)
Publication Date Accepted for publication: 28 March 1999
Full Text Language English
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Keywords Diabetes, glycogen metabolism, glycogen phosphorylase, structure-assisted drug design, inhibitors, x-ray crystallography.
Other Terms review article
Summary The three-dimensional structure of T-state glycogen phosphorylase in complex with α-D-glucose has been used as the starting point for the design and synthesis of a series of glucose analogues inhibitors that bind at the catalytic site of the enzyme and can act as powerful regulators of liver glycogen metabolism. The best compound to date exhibits a KI that is 3 orders of magnitude lower than that of glucose (K1=1.7 mM). In addition, as part of a screening process at Bayer AG, (-)3-isopropyl-4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methylpyridine-3,5,6-tricarboxylate was found to be the most potent inhibitor known to date of glycogen phosphorylase (K1=1.6 nM) that binds at the allosteric site of the enzyme and is effective in lowering blood glucose levels in rats.
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