Interactions at the bilayer interface and receptor site induced by the novel synthetic pyrrolidinone analog MMK3 |
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Authors: | C Fotakis E Siapi K Viras CG Kokotos S Golic Grdadolnik M Rappolt T Mavromoustakos |
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Institution: | a Chemistry Department, National and Kapodistrian University of Athens, Panepistimioupolis Zographou 15771, Greece b Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Vas. Constantinou 48, Athens 11635, Greece c Department of Biology, Chemistry and Pharmacy, Free University of Berlin, 14195 Berlin, Germany d Department of Biological Sciences, Institute for Biocomplexity and Informatics, University of Calgary, 2500 University Dr, Calgary, Alberta, T2N1N4 Canada e Laboratory of Biomolecular Structure, National Institute of Chemistry, 1001 Ljubljana, Slovenia f Institute of Biophysics and Nanosystems Research, Austrian Academy of Science, 8042 Graz, Austria |
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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 (AT1). 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 AT1 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. |
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Keywords: | Partial interdigitation Lipid bilayer MMK3 AT1 receptor Dipalmitoylphosphatidylcholine |
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