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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Conformational Analysis of Aliskiren, a Potent Renin Inhibitor,in Solution using Nuclear Magnetic Resonance (NMR) andMolecular Dynamics (MD)Minos–Timotheos Matsoukas 1 , Panagiotis Zoumpoulakis 2 ,and Theodore Tselios 11 University of Patras, Department of Chemistry, Patras, GR-26500, Greece; 2 Laboratoryof Molecular Analysis, Institute of Organic and Pharmaceutical Chemistry,National Hellenic Research Foundation, Athens, GR - 11635, GreeceIntroductionAliskiren [1] is a non-peptidic molecule that specifically and potently inhibits human renin(Figure 1). It has been newly introduced to the pharmaceutical industry as a standaloneantihypertensive drug with various effects, especially blockade of the renin receptor. Inprevious studies, 1D NMR experiments have been performed on aliskiren [2], but nostructural data is available in terms of its structural characteristics in solution. In this report,the conformational behavior of aliskiren is studied in water (H 2 O) and N,N-dimethylformamide(DMF) solutions, through High Resolution 600MHz NMR spectroscopy, bymeans of 2D-NMR spectroscopy [3] and molecular modeling techniques. Data extracted onthe interatomic distances between distant protons of the molecule’s functional groups arecombined with molecular dynamics simulations for inspection and evaluation of the drug’smolecular properties.Results and DiscussionNMR spectra were recorded on a Varian 600 MHz spectrometer (Figure 2). The sampleconcentration was kept ca. 10 mM dissolved in D 2 O and DMF-d 7 . Interatomicproton-proton distances werecalculated using the two-spinapproximation, and the integratedcross peaks intensity of a pair ofadjacent aromatic protons wasassumed to have a distance of 2.46Å. The resulting distances werecorrected for the frequency offseteffects to be eliminated. Upper andlower limit values of constraintswere allowed (10% of toleration).The conformational space ofFig. 1. Chemical structure of Aliskiren.aliskiren was explored usingFig. 2. 2D ROESY spectrum with interproton distances highlighted, obtained in DMF at25 °C (region 0-4.0 ppm).252