Aquaporins are integral membrane proteins from a larger family of major intrinsic proteins with previously unknown structures. Aquaporins (water channels) selectively conduct water molecules in and out of the cell while preventing the passage of ions and other solutes. Acetazolamide, Zonisamide, Bumetanide, AQB013, Arbidol, and Tamarixetin are reported aquaporin inhibitors that display high activity against aquaporin 1, 4, and 5 (Fig. 1).
Life Chemicals has designed its Aquaporin Targeted Library of over 2,000 small-molecule screening compounds with a receptor-based approach.
Our interest was focused on binding sites 3 and 1 [1, 2]. To delimit possible aquaporin ligand binding sites, the FTMap server was used. FTMap is an on-line tool for binding site search, visual localization of molecular probes (small molecules or functional groups) in the site volume, and solvent mapping of the surfaces. Overlapping of molecular probe clusters points at a potential binding site location. Flexible Glide docking was used to prepare aquaporin 1, 4, and 5 docking grids and constraints for subsequent ligand screening mode against the Life Chemicals HTS Compound Collection. After that, three ligand binding sites were processed and prepared for the docking of a test compound set. Minimization of docked ligand poses and binding site amino acids within contact distance was carried out in SYBYL-X.
Based on the docking poses of the test set of compounds, 4 docking models have been built for site1 and site3 of aquaporin 1, 4, and 5 (Fig. 1, 2). Selected potential aquaporin ligands were sorted by score value and binding site accessory - aq1,4 (these two were combined as their structures are very similar) site1 - 607, site3 - 340, aq5 site1 - 724, site3 – 343.
Subsets of compounds related to each target are presented separately.
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Figure 1. Docked conformation of known aquaporin inhibitors AQB013 (left), Arbidol (center), and Tamarixetin (left) in the binding site of Aquaporin 4. Atoms and regions predicted to form donor/acceptor interactions with ligand atoms and hydrophobic cores are indicated.
Figure 2. Solvent-accessible surface representation of binding site cavities of Aquaporin-4 (left) and Aquaporin-5 (right).
- Small-molecule inhibitors of NMO-IgG binding to aquaporin-4 reduce astrocyte cytotoxicity in neuromyelitisoptica. LukmaneeTradtrantip, Hua Zhang. 0892-6638/12/0026-2197 © FASEB
- Inhibition of Aquaporin-1 and Aquaporin-4 Water Permeability by a Derivative of the Loop Diuretic Bumetanide Acting at an Internal Pore-Occluding Binding Site. Elton Migliati, Nathalie Meurice. Molecular pharmacology Vol. 76, No. 1