The Application of REDOR NMR to Understand the Conformation of Epothilone B
AbstractThe 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. View Full-Text
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Lee, J.-H.; Kim, M.-S.; Lee, H.W.; Lee, I.-Y.C.; Kim, H.K.; Kim, N.D.; Lee, S.; Seo, H.; Paik, Y. The Application of REDOR NMR to Understand the Conformation of Epothilone B. Int. J. Mol. Sci. 2017, 18, 1472.
Lee J-H, Kim M-S, Lee HW, Lee I-YC, Kim HK, Kim ND, Lee S, Seo H, Paik Y. The Application of REDOR NMR to Understand the Conformation of Epothilone B. International Journal of Molecular Sciences. 2017; 18(7):1472.Chicago/Turabian Style
Lee, Jae-Ho; Kim, Moon-Su; Lee, Hyo W.; Lee, Ihl-Young C.; Kim, Hyun K.; Kim, Nam D.; Lee, SangGap; Seo, Hwajeong; Paik, Younkee. 2017. "The Application of REDOR NMR to Understand the Conformation of Epothilone B." Int. J. Mol. Sci. 18, no. 7: 1472.
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