Conformational Analysis of the cis‐ and trans‐Isomers of FK506 by NMR and Molecular Dynamics

Dale F. Mierke, Peter Schmieder, Peter Karuso, Horst Kessler

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The potent immunosuppressant drug FK506 (2) has been examined by 1H‐ and 13C‐NMR spectroscopy and NOE‐restrained molecular dynamics to elucidate the conformation in solution. A combination of two‐ and three‐dimensional NMR techniques was used to completely assign the 1H‐ and 13C‐NMR chemical shifts of the two configurational isomers resulting from the cis‐trans isomerization about the single amide bond. Hetero‐ and homonuclear coupling constants were measured to assign the diastereotopic methylene protons at C(16), C(18), and C(23). Intramolecular HH distances were defined from NOESY spectra recorded at −30° in CDCl3 and used as constraints in molecular‐dynamics simulations. The conformational preferences of 2 in solution are discussed in light of the constitutional features recently proposed to be necessary for binding and activity.

LanguageEnglish
Pages1027-1047
Number of pages21
JournalHelvetica Chimica Acta
Volume74
Issue number5
DOIs
Publication statusPublished - 1991

Fingerprint

Tacrolimus
Molecular Dynamics Simulation
Isomers
Molecular dynamics
isomers
Nuclear magnetic resonance
molecular dynamics
nuclear magnetic resonance
Chemical shift
Immunosuppressive Agents
Isomerization
Amides
Nuclear magnetic resonance spectroscopy
Conformations
Protons
Magnetic Resonance Spectroscopy
methylene
amides
isomerization
chemical equilibrium

Cite this

Mierke, Dale F. ; Schmieder, Peter ; Karuso, Peter ; Kessler, Horst. / Conformational Analysis of the cis‐ and trans‐Isomers of FK506 by NMR and Molecular Dynamics. In: Helvetica Chimica Acta. 1991 ; Vol. 74, No. 5. pp. 1027-1047.
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Conformational Analysis of the cis‐ and trans‐Isomers of FK506 by NMR and Molecular Dynamics. / Mierke, Dale F.; Schmieder, Peter; Karuso, Peter; Kessler, Horst.

In: Helvetica Chimica Acta, Vol. 74, No. 5, 1991, p. 1027-1047.

Research output: Contribution to journalArticleResearchpeer-review

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