Understanding the Inhibitory Effect of Highly Potent and Selective Archazolides Binding to the Vacuolar ATPase

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• 作者：Sandra Dreisigacker ; Dorota Latek ; Svenja Bockelmann ; Markus Huss ; Helmut Wieczorek ; Slawomir Filipek ; Holger Gohlke ; Dirk Menche ; Teresa Carlomagno
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2012
• 出版时间：August 27, 2012
• 年：2012
• 卷：52
• 期：8
• 页码：2265-2272
• 全文大小：437K
• 年卷期：v.52,no.8(August 27, 2012)
• ISSN：1549-960X

文摘

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 V_O-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.