title: Interactions at the bilayer interface and receptor site induced by the novel synthetic pyrrolidinone analog MMK3.
abstract: This work presents a thorough investigation of the interaction of the novel synthetic pyrrolidinone analog MMK3 with the model membrane system of dipalmitoylphosphatidylcholine (DPPC) and the receptor active site. MMK3 has been designed to exert antihypertensive activity by functioning as an antagonist of the angiotensin II receptor of subtype 1 (AT(1)). Its low energy conformers were characterized by 2D rotating-frame Overhauser effect spectroscopy (ROESY) in combination with molecular dynamics (MD) simulations. Docking study of MMK3 shows that it fits to the AT(1) receptor as SARTANs, however, its biological activity appears to be lower. Thus, differential scanning calorimetry (DSC), Raman spectroscopy and small angle X-ray scattering (SAXS) experiments on the interaction of MMK3 with DPPC bilayers were carried out and results demonstrate that the drug is well incorporated into the membrane leaflets and furthermore causes partial bilayer interdigitation, although less effective than SARTANs. Thus, it appears that the nature of the bilayer matrix and the stereoelectronic active site requirements of the receptor are responsible for the low bioactivity of MMK3.
authors.affiliation: Chemistry Department, National and Kapodistrian University of Athens, Panepistimioupolis Zographou 15771, Greece.
authors.forename: C
authors.initials: C
authors.lastname: Fotakis
authors.forename: S
authors.initials: S
authors.lastname: Gega
authors.forename: E
authors.initials: E
authors.lastname: Siapi
authors.forename: C
authors.initials: C
authors.lastname: Potamitis
authors.forename: K
authors.initials: K
authors.lastname: Viras
authors.forename: P
authors.initials: P
authors.lastname: Moutevelis-Minakakis
authors.forename: C G
authors.initials: CG
authors.lastname: Kokotos
authors.forename: S
authors.initials: S
authors.lastname: Durdagi
authors.forename: S Golic
authors.initials: SG
authors.lastname: Grdadolnik
authors.forename: B
authors.initials: B
authors.lastname: Sartori
authors.forename: M
authors.initials: M
authors.lastname: Rappolt
authors.forename: T
authors.initials: T
authors.lastname: Mavromoustakos
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine; D002152:Calorimetry, Differential Scanning; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism*; D008051:Lipid Bilayers / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D017433:Protein Structure, Secondary; D011522:Protons; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism*; D011760:Pyrrolidinones / Q000737:chemistry*; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013059:Spectrum Analysis, Raman; D013696:Temperature; D014961:X-Ray Diffraction
chemical_list: D007093:Imidazoles; D008051:Lipid Bilayers; C512492:MMK3 compound; D011522:Protons; D011759:Pyrrolidines; D011760:Pyrrolidinones; D011945:Receptors, Angiotensin; D015060:1,2-Dipalmitoylphosphatidylcholine