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 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.
Original language | English |
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Pages (from-to) | 2265-72 |
Number of pages | 8 |
Journal | Journal of Chemical Information and Modeling |
Volume | 52 |
Issue number | 8 |
DOIs | |
Publication status | Published - 27 Aug 2012 |
Keywords
- Animals
- Cell Line
- Enzyme Inhibitors/chemistry
- Inhibitory Concentration 50
- Macrolides/chemistry
- Mice
- Molecular Docking Simulation
- Molecular Dynamics Simulation
- Protein Binding
- Protein Structure, Secondary
- Reproducibility of Results
- Saccharomyces cerevisiae/enzymology
- Substrate Specificity
- Thiazoles/chemistry
- Vacuolar Proton-Translocating ATPases/antagonists & inhibitors