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

作者：Dreisigacker Sandra; Latek Dorota; Bockelmann Svenja; Huss Markus; Wieczorek Helmut; Filipek Slawomir; Gohlke Holger; Menche Dirk; Carlomagno Teresa^*

来源：Journal of Chemical Information and Modeling, 2012, 52(8): 2265-2272.

DOI：10.1021/ci300242d

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 sub-nanomolar 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.

• 出版日期2012-8