Understanding the inhibitory effect of highly potent and selective archazolides binding to the vacuolar ATPase

• Verfasst von: Dreisigacker, Sandra [VerfasserIn]
• Verfasst von: Menche, Dirk [VerfasserIn]
• Titel: Understanding the inhibitory effect of highly potent and selective archazolides binding to the vacuolar ATPase
• Verf.angabe: Sandra Dreisigacker, Dorota Latek, Svenja Bockelmann, Markus Huss, Helmut Wieczorek, Slawomir Filipek, Holger Gohlke, Dirk Menche, Teresa Carlomagno
• E-Jahr: 2012
• Jahr: 27 August 2012
• Umfang: 8 S.
• Fussnoten: Gesehen am 29.11.2018
• Titel Quelle: Enthalten in: Journal of chemical information and modeling
• Ort Quelle: Washington, DC : American Chemical Society, 1975
• Jahr Quelle: 2012
• Band/Heft Quelle: 52(2012), 8, Seite 2265-2272
• ISSN Quelle: 1549-960X
• DOI: doi:10.1021/ci300242d
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1584624841

Abstract

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.