Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	The s-Hole Phenomenon of Halogen Atoms Forms the Structural Basis of the Strong Inhibitory Potency of C5 Halogen Substituted Glucopyranosyl Nucleosides towards Glycogen Phosphorylase b
Δημιουργός/Συγγραφέας:	Kantsadi, Anastasia L. Hayes, Joseph M. Manta, Stella Skamnaki, Vicky T. Kiritsis, Christos Psarra, Anna-Maria G. Koutsogiannis, Zissis Dimopoulou, Athina Theofanous, Stavroula Nikoleousakos, Nikolaos [EL] Ζουμπουλάκης, Παναγιώτης[EN] Zoumpoulakis, Panagiotis Kontou, Maria Papadopoulos, George [EL] Ζωγράφος, Σπύρος Ε.[EN] Zographos, Spyros E. Komiotis, Dimitris [EL] Λεωνίδας, Δημήτρης Δ.[EN] Leonidas, Demetres D.
Εκδότης:	Wiley-v C H Verlag Gmbh
Τόπος έκδοσης:	Weinheim
Ημερομηνία:	2012-04
Γλώσσα:	Αγγλικά
ISSN:	1860-7179
Περίληψη:	C5 halogen substituted glucopyranosyl nucleosides (1-(beta-D-glucopyranosyl)-5-X-uracil; X=Cl, Br, I) have been discovered as some of the most potent active site inhibitors of glycogen phosphorylase (GP), with respective Ki values of 1.02, 3.27, and 1.94 mu M. The ability of the halogen atom to form intermolecular electrostatic interactions through the s-hole phenomenon rather than through steric effects alone forms the structural basis of their improved inhibitory potential relative to the unsubstituted 1-(beta-D-glucopyranosyl)uracil (Ki=12.39 mu M), as revealed by X-ray crystallography and modeling calculations exploiting quantum mechanics methods. Good agreement was obtained between kinetics results and relative binding affinities calculated by QM/MM-PBSA methodology for various substitutions at C5. Ex vivo experiments demonstrated that the most potent derivative (X=Cl) toward purified GP has no cytotoxicity and moderate inhibitory potency at the cellular level. In accordance, ADMET property predictions were performed, and suggest decreased polar surface areas as a potential means of improving activity in the cell.
Τίτλος πηγής δημοσίευσης:	Chemmedchem
Τόμος/Κεφάλαιο:	7
Τεύχος:	4
Σελίδες:	722-732
Θεματική Κατηγορία:	[EL] Χημεία (Γενικά)[EN] Chemistry (General) [EL] Φαρμακευτική[EN] Pharmacy and materia medica
Λέξεις-Κλειδιά:	biological chemistry chemical biology glycogen phosphorylase halogen bonding QM MM-PBSA X-ray diffraction Chemistry, Medicinal
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
Κάτοχος πνευματικών δικαιωμάτων:	© WILEY-V C H VERLAG GMBH
ΙΒΦΧΒ: αρχειακή συλλογή:	Ινστιτούτο Οργανικής και Φαρμακευτικής Χημείας (ΙΟΦΧ) (έως 2012)
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο