Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 20, Issue 44, Pages 14201-14206Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201403839
Keywords
Cilengitide; conformational analysis; NMR spectroscopy; peptides; X-ray crystallography
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Funding
- DFG
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The X-ray crystal and NMR spectroscopic structures of the peptide drug candidate Cilengitide (cyclo(RGDf(NMe)Val)) in various solvents are obtained and compared in addition to the integrin receptor bound conformation. The NMR-based solution structures exhibit conformations closely resembling the X-ray structure of Cilengitide bound to the head group of integrin v3. In contrast, the structure of pure Cilengitide recrystallized from methanol reveals a different conformation controlled by the lattice forces of the crystal packing. Molecular modeling studies of the various ligand structures docked to the v3 integrin revealed that utilization of the solid-state conformation of Cilengitide leadsunlike the solution-based structuresto a mismatch of the ligand-receptor interactions compared with the experimentally determined structure of the protein-ligand complex. Such discrepancies between solution and crystal conformations of ligands can be misleading during the structure-based lead optimization process and should thus be taken carefully into account in ligand orientated drug design.
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