Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	3 '-Axial CH2OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM-PBSA Calculations Suggest Why
Δημιουργός/Συγγραφέας:	Manta, Stella Xipnitou, Andromachi Kiritsis, Christos Kantsadi, Anastassia L. Hayes, Joseph M. Skamnaki, Vicky T. Lamprakis, Christos Kontou, Maria [EL] Ζουμπουλάκης, Παναγιώτης[EN] Zoumpoulakis, Panagiotis [EL] Ζωγράφος, Σπύρος Ε.[EN] Zographos, Spyros E. [EL] Λεωνίδας, Δημήτρης Δ.[EN] Leonidas, Demetres D. Komiotis, Dimitri
Εκδότης:	Wiley-blackwell
Τόπος έκδοσης:	Malden
Ημερομηνία:	2012-05
Γλώσσα:	Αγγλικά
ISSN:	1747-0277
DOI:	10.1111/j.1747-0285.2012.01349.x
Περίληψη:	Glycogen phosphorylase is a molecular target for the design of potential hypoglycemic agents. Structure-based design pinpointed that the 3'-position of glucopyranose equipped with a suitable group has the potential to form interactions with enzymes cofactor, pyridoxal 5'-phosphate (PLP), thus enhancing the inhibitory potency. Hence, we have investigated the binding of two ligands, 1-(beta-d-glucopyranosyl)5-fluorouracil (GlcFU) and its 3'-CH2OH glucopyranose derivative. Both ligands were found to be low micromolar inhibitors with K-i values of 7.9 and 27.1 mu m, respectively. X-ray crystallography revealed that the 3'-CH2OH glucopyranose substituent is indeed involved in additional molecular interactions with the PLP gamma-phosphate compared with GlcFU. However, it is 3.4 times less potent. To elucidate this discovery, docking followed by postdocking Quantum Mechanics/Molecular Mechanics PoissonBoltzmann Surface Area (QM/MM-PBSA) binding affinity calculations were performed. While the docking predictions failed to reflect the kinetic results, the QM/MM-PBSA revealed that the desolvation energy cost for binding of the 3'-CH2OH-substituted glucopyranose derivative out-weigh the enthalpy gains from the extra contacts formed. The benefits of performing postdocking calculations employing a more accurate solvation model and the QM/MM-PBSA methodology in lead optimization are therefore highlighted, specifically when the role of a highly polar/charged binding interface is significant.
Τίτλος πηγής δημοσίευσης:	Chemical Biology & Drug Design
Τόμος/Κεφάλαιο:	79
Τεύχος:	5
Σελίδες:	663-673
Θεματική Κατηγορία:	[EL] Βιολογία (Γενικά)[EN] Biology (General) [EL] Χημεία (Γενικά)[EN] Chemistry (General) [EL] Φαρμακευτική[EN] Pharmacy and materia medica
Λέξεις-Κλειδιά:	branched C-hydroxymethyl nucleosides enzyme inhibition glide docking glycogen phosphorylase QM MM-PBSA solvation modeling type 2 diabetes X-ray crystallography Chemistry, Medicinal
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
Όροι και προϋποθέσεις δικαιωμάτων:	Free access by the publisher. This article appears in "Chemical Biology & Drug Design, vol. 79, no. 5, pp. 663-673, May 2012" and can be found at the following on Wiley Online Library : https://doi.org/10.1111/j.1747-0285.2012.01349.x
ΙΒΦΧΒ: αρχειακή συλλογή:	Ινστιτούτο Οργανικής και Φαρμακευτικής Χημείας (ΙΟΦΧ) (έως 2012)
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο