Understanding the inhibitory effect of highly potent and selective archazolides binding to the vacuolar ATPase
Vacuolar ATPases are a potential therapeutic target because of their involvement in a variety of severe diseases such as osteoporosis or cancer. Archazolide A (1) and related analogs have been previously identified as selective inhibitors of V-ATPases with potency down to the subnanomolar range. Here...
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| Hauptverfasser: | , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
27 August 2012
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| In: |
Journal of chemical information and modeling
Year: 2012, Jahrgang: 52, Heft: 8, Pages: 2265-2272 |
| ISSN: | 1549-960X |
| DOI: | 10.1021/ci300242d |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1021/ci300242d Verlag, Volltext: http://pubs.acs.org/doi/10.1021/ci300242d 
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| Verfasserangaben: | Sandra Dreisigacker, Dorota Latek, Svenja Bockelmann, Markus Huss, Helmut Wieczorek, Slawomir Filipek, Holger Gohlke, Dirk Menche, Teresa Carlomagno |
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| 520 | |a Vacuolar ATPases are a potential therapeutic target because of their involvement in a variety of severe diseases such as osteoporosis or cancer. Archazolide A (1) and related analogs have been previously identified as selective inhibitors of V-ATPases with potency down to the subnanomolar range. Herein we report on the determination of the ligand binding mode by a combination of molecular docking, molecular dynamics simulations, and biochemical experiments, resulting in a sound model for the inhibitory mechanism of this class of putative anticancer agents. The binding site of archazolides was confirmed to be located in the equatorial region of the membrane-embedded VO-rotor, as recently proposed on the basis of site-directed mutagenesis. Quantification of the bioactivity of a series of archazolide derivatives, together with the docking-derived binding mode of archazolides to the V-ATPase, revealed favorable ligand profiles, which can guide the development of a simplified archazolide analog with potential therapeutic relevance. | ||
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