Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Insights into the molecular basis of action of the AT1 antagonist losartan using a combined NMR spectroscopy and computational approach
Δημιουργός/Συγγραφέας:	[EL] Ζερβού, Μαρία[EN] Zervou, Maria Cournia Z. Potamitis C. Patargias G. Durdagi S. Grdadolnik S.G. [EL] Μαυρομούστακος, Θωμάς[EN] Mavromoustakos, Thomas
Εκδότης:	Elsevier B.V.
Ημερομηνία:	2014
Γλώσσα:	Αγγλικά
ISSN:	0005-2736
DOI:	10.1016/j.bbamem.2013.12.012
Άλλο:	PubMed ID: 24374319
Περίληψη:	The drug:membrane interactions for the antihypertensive AT1 antagonist losartan, the prototype of the sartans class, are studied herein using an integrated approach. The pharmacophore arrangement of the drug was revealed by rotating frame nuclear Overhauser effect spectroscopy (2D ROESY) NMR spectroscopy in three different environments, namely water, dimethyl sulfoxide (DMSO), and sodium dodecyl sulfate (SDS) micellar solutions mimicking conditions of biological transport fluids and membrane lipid bilayers. Drug association with micelles was monitored by diffusion ordered spectroscopy (2D DOSY) and drug:micelle intermolecular interactions were characterized by ROESY spectroscopy. The localisation of the drug in the micellar environment was investigated by introducing 5-doxyl and 16-doxyl stearic acids. The use of spin labels confirmed that losartan resides close to the micelle:water interface with the hydroxymethyl group and the tetrazole heterocyclic aromatic ring facing the polar surface with the potential to interact with SDS charged polar head groups in order to increase amphiphilic interactions. The spontaneous insertion, the diffusion pathway and the conformational features of losartan were monitored by Molecular Dynamics (MD) simulations in a modeled SDS micellar aggregate environment and a long exploratory MD run (580 ns) in a phospholipid dipalmitoylphosphatidylcholine (DPPC) bilayer with the AT1 receptor embedded. MD simulations were in excellent agreement with experimental results and further revealed the molecular basis of losartan:membrane interactions in atomic-level detail. This applied integrated approach aims to explore the role of membranes in losartan's pathway towards the AT1 receptor.
Τίτλος πηγής δημοσίευσης:	Biochimica et Biophysica Acta - Biomembranes
Τόμος/Κεφάλαιο:	1838
Τεύχος:	3
Σελίδες:	1031-1046
Θεματική Κατηγορία:	[EL] Φαρμακευτική χημεία[EN] Pharmaceutical chemistry
Λέξεις-Κλειδιά:	Losartan Molecular dynamics in micelles NMR (DOSY, NOESY/ROESY) SDS micelles Spin labels
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
Κάτοχος πνευματικών δικαιωμάτων:	© 2013 Elsevier B.V.
Όροι και προϋποθέσεις δικαιωμάτων:	All Open Access, Bronze
Σημειώσεις:	Seventh Framework Programme, FP7: 245866; Seventh Framework Programme, FP7: FP7-REGPOT-2009-1
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο