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The Application of REDOR NMR to Understand the Conformation of Epothilone B
- Source :
- International Journal of Molecular Sciences, Vol 18, Iss 7, p 1472 (2017), International Journal of Molecular Sciences; Volume 18; Issue 7; Pages: 1472, International Journal of Molecular Sciences
- Publication Year :
- 2017
- Publisher :
- MDPI AG, 2017.
-
Abstract
- The structural information of small therapeutic compounds complexed in biological matrices is important for drug developments. However, structural studies on ligands bound to such a large and dynamic system as microtubules are still challenging. This article reports an application of the solid-state NMR technique to investigating the bioactive conformation of epothilone B, a microtubule stabilizing agent, whose analog ixabepilone was approved by the U.S. Food and Drug Administration (FDA) as an anticancer drug. First, an analog of epothilone B was designed and successfully synthesized with deuterium and fluorine labels while keeping the high potency of the drug; Second, a lyophilization protocol was developed to enhance the low sensitivity of solid-state NMR; Third, molecular dynamics information of microtubule-bound epothilone B was revealed by high-resolution NMR spectra in comparison to the non-bound epothilone B; Last, information for the macrolide conformation of microtubule-bound epothilone B was obtained from rotational-echo double-resonance (REDOR) NMR data, suggesting the X-ray crystal structure of the ligand in the P450epoK complex as a possible candidate for the conformation. Our results are important as the first demonstration of using REDOR for studying epothilones.
- Subjects :
- Epothilones
Magnetic Resonance Spectroscopy
Stereochemistry
Molecular Conformation
microtubules
epothilone B
REDOR
solid-state NMR
bioactive conformation
Crystallography, X-Ray
010402 general chemistry
01 natural sciences
Article
Catalysis
Inorganic Chemistry
lcsh:Chemistry
03 medical and health sciences
chemistry.chemical_compound
Molecular dynamics
0302 clinical medicine
Physical and Theoretical Chemistry
Molecular Biology
lcsh:QH301-705.5
Spectroscopy
United States Food and Drug Administration
Ligand
Organic Chemistry
Ixabepilone
General Medicine
Combinatorial chemistry
Anticancer drug
United States
0104 chemical sciences
Computer Science Applications
NMR spectra database
Solid-state nuclear magnetic resonance
chemistry
Epothilone B
lcsh:Biology (General)
lcsh:QD1-999
030220 oncology & carcinogenesis
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Volume :
- 18
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....4cf793e1f4bae7e955add401bdad73bd