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Three‐dimensional structure of cyclic antibiotic teicoplanin aglycone using NMR distance and dihedral angle restraints in a DMSO solvation model
Authors:Nina C Gonnella  Nelu Grinberg  Mark Mcloughlin  Om Choudhary  Keith Fandrick  Shengli Ma
Institution:1. Materials and Analytical Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA;2. Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
Abstract:The three‐dimensional solution conformation of teicoplanin aglycone was determined using NMR spectroscopy. A combination of NOE and dihedral angle restraints in a DMSO solvation model was used to calculate an ensemble of structures having a root mean square deviation of 0.17 Å. The structures were generated using systematic searches of conformational space for optimal satisfaction of distance and dihedral angle restraints. Comparison of the NMR‐derived structure of teicoplanin aglycone with the X‐ray structure of a teicoplanin aglycone analog revealed a common backbone conformation with deviation of two aromatic side chain substituents. Experimentally determined backbone 13C chemical shifts showed good agreement with those computed at the density functional level of theory, providing a cross validation of the backbone conformation. The flexible portion of the molecule was consistent with the region that changes conformation to accommodate protein binding. The results showed that a hydrogen‐bonded DMSO molecule in combination with NMR‐derived restraints together enabled calculation of structures that satisfied experimental data. Copyright © 2015 John Wiley & Sons, Ltd.
Keywords:teicoplanin aglycone  nuclear magnetic resonance  conformation  3D structure  solvation model  density functional theory
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