title: Antihypertensive drug valsartan in solution and at the AT1 receptor: conformational analysis, dynamic NMR spectroscopy, in silico docking, and molecular dynamics simulations.
abstract: The conformational properties of AT1 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 approximately 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 AT1 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.
authors.affiliation: National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, Vas, Constantinou 48, 11635 Athens, Greece.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Potamitis
authors.forename: Maria
authors.initials: M
authors.lastname: Zervou
authors.forename: Vassilis
authors.initials: V
authors.lastname: Katsiaras
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Zoumpoulakis
authors.forename: Serdar
authors.initials: S
authors.lastname: Durdagi
authors.forename: Manthos G
authors.initials: MG
authors.lastname: Papadopoulos
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Hayes
authors.forename: Simona Golic
authors.initials: SG
authors.lastname: Grdadolnik
authors.forename: Ioanna
authors.initials: I
authors.lastname: Kyrikou
authors.forename: Dimitris
authors.initials: D
authors.lastname: Argyropoulos
authors.forename: Georgia
authors.initials: G
authors.lastname: Vatougia
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
mesh_terms: D000959:Antihypertensive Agents / Q000737:chemistry*; D008051:Lipid Bilayers; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011945:Receptors, Angiotensin / Q000737:chemistry*; D013777:Tetrazoles / Q000737:chemistry*; D014633:Valine / Q000031:analogs & derivatives* / Q000737:chemistry; D000068756:Valsartan
chemical_list: D000959:Antihypertensive Agents; D008051:Lipid Bilayers; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine