In structure-based drug design, the relative orientation of two competitive ligands A and B in the receptor binding pocket plays a central role in the design of high-affinity drug candidates from weakly bound lead compounds. In this communication we report on the observation of interligand spin-diffusion-mediated transferred-NOE data, which have the potential to be used for the determination of the relative orientation of two competitive ligands in the receptor binding pocket. In many cases, the orientation of one ligand in the binding pocket is known, for example, from crystallography or fluorescence resonance energy transfer (FRET) data. In these cases it is desirable to develop a methodology that allows the determination of a unique binding mode and pharmacophore model for a second competitive ligand. We anticipate that the interligand transferred NOEs described here could provide the experimental basis for a methodology that is applicable to any combination of ligands weakly bound to a common receptor.The conformation of a ligand in the binding pocket of a macromolecular receptor can be accessed by NMR spectroscopy in solution by two approaches. If the molecular weight of the complex is of the order of 50 kDa or smaller and 13 C/ 15 Nlabeled receptor can be produced in vitro, a detailed threedimensional picture of the ligand and of its interactions with the receptor binding pocket can be obtained with standard NMR spectroscopy methods.[1] However, in other cases the macromolecular receptor is too large for NMR studies in solution or it cannot be synthesized in vitro to introduce NMR-active isotopes. In these instances, NMR spectroscopy[*] Dr.

Passt in eine Tasche: Die Art der Bindung von Epothilon A (EpoA) an Tubulin (siehe Bild; Stäbchen: C grau, H weiß, N blau, O rot, S gelb) wurde NMR‐spektroskopisch in wässriger Lösung bestimmt. Die Ergebnisse bieten eine Erklärung für die bekannten Struktur‐Aktivitäts‐Beziehungen von Epothilonen für native wie mutante Tubuline und stützen das Vorliegen eines gemeinsamen Pharmakophors für EpoA und Paclitaxel.

No abstract

A procedure for the direct use of (1)D(CH) residual dipolar couplings (RDCs) from freely rotating groups in the structural analysis of small molecules was implemented. (1)D(CH) RDCs were used to determine both the preferred conformation and the stereochemical assignment of the diastereotopic geminal methyls of 8-phenylmenthol. Furthermore, a method was also set up to fit RDC data to a set of conformations in solution on the assumption that they all have the same alignment tensor.

In structure-based drug design, the relative orientation of two competitive ligands A and B in the receptor binding pocket plays a central role in the design of high-affinity drug candidates from weakly bound lead compounds. In this communication we report on the observation of interligand spin-diffusion-mediated transferred-NOE data, which have the potential to be used for the determination of the relative orientation of two competitive ligands in the receptor binding pocket. In many cases, the orientation of one ligand in the binding pocket is known, for example, from crystallography or fluorescence resonance energy transfer (FRET) data. In these cases it is desirable to develop a methodology that allows the determination of a unique binding mode and pharmacophore model for a second competitive ligand. We anticipate that the interligand transferred NOEs described here could provide the experimental basis for a methodology that is applicable to any combination of ligands weakly bound to a common receptor.The conformation of a ligand in the binding pocket of a macromolecular receptor can be accessed by NMR spectroscopy in solution by two approaches. If the molecular weight of the complex is of the order of 50 kDa or smaller and 13 C/ 15 Nlabeled receptor can be produced in vitro, a detailed threedimensional picture of the ligand and of its interactions with the receptor binding pocket can be obtained with standard NMR spectroscopy methods.[1] However, in other cases the macromolecular receptor is too large for NMR studies in solution or it cannot be synthesized in vitro to introduce NMR-active isotopes. In these instances, NMR spectroscopy[*] Dr.

The use of the cetylpyridinium chloride (CPCL)/NaCl/hexanol liquid crystal allowed the measurement of (1)D(CH) residual dipolar couplings of the isoquinoline alkaloid salsolidine in its protonated state. Populations of its two half-chair forms were determined by using the single alignment tensor approximation combined with global superposition of conformers. These populations were in good agreement with the DFT-computed energies for both conformers.

Bound to have similarities: Although the overall shape of discodermolide bound to tubulin resembles the structure of the free ligand, the precise conformation and orientation of the lactone ring are different. A partially overlapping pharmacophore model supported by protein‐mediated interligand NOE signals (see picture) is proposed to explain the similar (but not fully equivalent) biological activity of discodermolide and epothilone A.

Ähnlichkeit gesucht: Trotz ähnlicher Gesamtform von Discodermolid als freier Ligand und in der Bindung an Tubulin gibt es Unterschiede in der genauen Konformation und Orientierung des Lactonrings. Ein Modell des partiell überlappenden Pharmakophors, das von proteinvermittelten Interligand‐NOE‐Signalen (siehe Bild) unterstützt wird, soll die ähnlichen (aber nicht ganz äquivalenten) biologischen Aktivitäten von Discodermolid und Epothilon A erklären.