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Antihypertensive Drug Valsartan in Solution and at the AT(1) Receptor: Conformational Analysis, Dynamic NMR Spectroscopy, in Silico Docking, and Molecular Dynamics Simulations

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Antihypertensive Drug Valsartan in Solution and at the AT(1) Receptor: Conformational Analysis, Dynamic NMR Spectroscopy, in Silico Docking, and Molecular Dynamics Simulations
Durdagi, Serdar
Παπαδόπουλος, Μάνθος Γ.
Μαυρομούστακος, Θωμάς
Hayes, Joseph M.
Argyropoulos, Dinutris
Kyrikou, Ioanna
Grdadolnik, Simona Golic
Potamitis, Constantinos
Ζουμπουλάκης, Παναγιώτης
Katsiaras, Vassilis
Vatougia, Georgia
Ζερβού, Μαρία
Άρθρο σε επιστημονικό περιοδικό
2009-03
The conformational properties of AT, antagonist valsartan have been analyzed both in solution and at the binding site of the receptor. Low energy conformations of valsartan in solution were explored by NMR spectroscopy and molecular modeling studies. The NMR results showed the existence of two distinct and almost isoenergetic conformations for valsartan (cis: trans ratio around the amide bond similar to 40:60) that coalesce at the temperature range of 55-60 degrees C in agreement with previous in solution conformational analysis study (Fang et al. Magn. Reson. Chem. 2007, 45, 929-936). Quantum mechanics and ONIOM calculations revealed that the bulky valsartan substituents actually contribute to stabilization of the transition state for interconversion. In silico docking and Molecular Dynamic studies were applied to study binding of valsartan at the AT, receptor site models, explicitly solvated and embedded in lipid bilayers and solvent molecules. These studies revealed that the majority of docked poses adopted a trans (major) conformation. Of paramount and maybe biological importance are the MD simulations results which showed that the two acidic groups of valsartan are bridged through LYS199 enabling it for multiple hydrogen bond interactions. In a lipid bilayer environment these interactions are enhanced, designating the important role of lipid bilayers for the better binding of valsartan and its stabilization at the active site.
Washington
Ηλεκτρονικοί υπολογιστές. Επιστήμη των υπολογιστών (EL)
Χημεία (Γενικά) (EL)
Electronic computers. Computer science (EN)
Chemistry (General) (EN)
Computer Science, Information Systems
Computer Science, Interdisciplinary Applications
Chemistry, Multidisciplinary
English
American Chemical Society
Journal of Chemical Information and Modeling
© AMER CHEMICAL SOC
© AMER CHEMICAL SOC (EN)
Εθνικό Ίδρυμα Ερευνών (ΕΙΕ)
Ήλιος - Αποθετήριο Εθνικού Ιδρύματος Ερευνών



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