Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	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
Δημιουργός/Συγγραφέας:	Hayes, Joseph M. Skamnaki, Vicky T. Archontis, Georgios Lamprakis, Christos Sarrou, Josephine Bischler, Nicolas Skaltsounis, Alexios-Leandros [EL] Ζωγράφος, Σπύρος Ε.[EN] Zographos, Spyros E. [EL] Οικονομάκος, Νίκος Γ.[EN] Oikonomakos, Nikos G.
Εκδότης:	John Wiley & Sons, Inc.
Τόπος έκδοσης:	MALDEN
Ημερομηνία:	2011-03
Γλώσσα:	Αγγλικά
ISSN:	0887-3585
DOI:	10.1002/prot.22890
Περίληψη:	With an aim toward glycogenolysis control in Type 2 diabetes, we have investigated via kinetic experiments and computation the potential of indirubin (IC50 > 50 mu M), indirubin-3'-oxime (IC50 = 144 nM), KT5720 (K-i = 18.4 nM) and staurosporine (K-i = 0.37 nM) as phosphorylase kinase (PhK gamma trnc) ATP-binding site inhibitors, with the latter two revealed as potent inhibitors in the low nM range. Because of lack of structural information, we have exploited information from homologous kinase complexes to direct in silico calculations (docking, molecular dynamics, and MM-GBSA) to predict the binding characteristics of the four ligands. All inhibitors are predicted to bind in the same active site area as the ATP adenine ring, with binding dominated by hinge region hydrogen bonds to Asp104:O and Met106:O (all four ligands) and also Met106:NH (for the indirubins). The PhK gamma trnc-staurosporine complex has the greatest number of receptor-ligand hydrogen bonds, while for the indirubin-3'-oxime and KT5720 complexes there is an important network of interchanging water molecules bridging inhibitor-enzyme contacts. The MM-GBSA results revealed the source of staurosporine's low nM potency to be favorable electrostatic interactions, while KT5720 has strong van der Waals contributions. KT5720 interacts with the greatest number of protein residues either by direct or 1-water bridged hydrogen bond interactions, and the potential for more selective PhK inhibition based on a KT5720 analogue has been established. Including receptor flexibility in Schrodinger induced-fit docking calculations in most cases correctly predicted the binding modes as compared with the molecular dynamics structures; the algorithm was less effective when there were key structural waters bridging receptor-ligand contacts.
Τίτλος πηγής δημοσίευσης:	Proteins-structure Function and Bioinformatics
Τόμος/Κεφάλαιο:	79
Τεύχος:	3
Σελίδες:	703-719
Θεματική Κατηγορία:	[EL] Βιολογία (Γενικά)[EN] Biology (General) [EL] Φυσική[EN] Physics
Λέξεις-Κλειδιά:	type 2 diabetes protein kinase inhibitors induced-fit docking Desmond molecular dynamics receptor flexibility Biophysics
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
EU Grant identifier:	info:eu-repo/grantAgreement/EC/FP7/230146
Κάτοχος πνευματικών δικαιωμάτων:	© WILEY-BLACKWELL
Ηλεκτρονική διεύθυνση περιοδικού (link) :	http://www3.interscience.wiley.com/cgi-bin/jhome/36176
ΙΒΦΧΒ: αρχειακή συλλογή:	Ινστιτούτο Οργανικής και Φαρμακευτικής Χημείας (ΙΟΦΧ) (έως 2012)
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο