title: Understanding the inhibitory effect of highly potent and selective archazolides binding to the vacuolar ATPase.
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.
authors: Structural and Computational Biology Unit, EMBL, Mayerhofstrasse 1, D-69117 Heidelberg, Germany.
authors: Sandra
authors: S
authors: Dreisigacker
authors: Dorota
authors: D
authors: Latek
authors: Svenja
authors: S
authors: Bockelmann
authors: Markus
authors: M
authors: Huss
authors: Helmut
authors: H
authors: Wieczorek
authors: Slawomir
authors: S
authors: Filipek
authors: Holger
authors: H
authors: Gohlke
authors: Dirk
authors: D
authors: Menche
authors: Teresa
authors: T
authors: Carlomagno
mesh_terms: D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D015203:Reproducibility of Results; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013379:Substrate Specificity; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D018942:Macrolides; D013844:Thiazoles; C529652:archazolide A; D025262:Vacuolar Proton-Translocating ATPases