Aquaporins (AQPs) are integral membrane proteins that facilitate the selective and rapid transport of water and, in some cases, small solutes such as glycerol, urea, and hydrogen peroxide across cell membranes. These channels play pivotal roles in various physiological processes, including fluid homeostasis, kidney function, supporting brain water homeostasis and cell migration. Due to their involvement in numerous diseases, aquaporins have emerged as promising therapeutic targets. Manipulating aquaporin function presents a potential avenue for treating conditions associated with water imbalance, for example, edema, brain swelling, and kidney disorders [1].
Recent advances in structural biology, high-throughput screening and computational modeling have highlighted opportunities for targeting AQPs through drug discovery. The primary efforts aim to selectively modulate aquaporin activity, either by enhancing or inhibiting their function, tailored to address specific disease states. Acetazolamide, Zonisamide, Bumetanide, AQB013, Arbidol, and Tamarixetin are reported aquaporin inhibitors that display high activity against aquaporin 1, 4, and 5 (Fig. 1).
To facilitate aquaporin-focused drug discovery projects, Life Chemicals has prepared a dedicated Aquaporin Screening Compound Library of approximately 6,000 small molecules, selected through a receptor-based approach.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Representative screening compounds from the Aquaporin Screening Library
Aquaporins 1, 4, and 5
This Screening Set was designed with a focus on binding sites 3 and 1 [1, 2]. To delimit possible aquaporin ligand binding sites, the FTMap server was used. The FTMap is an online 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. The overlapping of molecular probe clusters points to a potential binding site location.
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.
Then, we prepared docking grids and constraints using the Flexible Glide docking for aquaporins 1, 4 and 5. These grids were used for ligand screening against the Life Chemicals HTS Compound Collection. It was followed by processing three ligand binding sites to facilitate docking with a set of test compounds. After that, the SYBYL-X was used to conduct minimization processes for the docked ligand poses and the amino acids within contact distance. Based on the docking poses of the test compounds, we constructed docking models for sites 1 and 3 of aquaporins 1, 4 and 5 (Fig. 1-2). Finally, the compound subsets related to every specific target were organized separately for further analysis.
Key features
- Method: molecular docking
- X-Ray data used: 3GD8
- Constraints: none
- Protein rotatable groups allowed: yes
- Filters used: PAINS, toxic, reactive
- Number of compounds selected: 1004
Figure 2. Representation of binding site cavity of Aquaporin-4 with the top-ranked compound F3260-0485 in binding site 1. Dots depict the pore surface, and residues involved in the binding process are colored dark gray.
AQP7
AQP7 is a member of the aquaporin family, a group of membrane proteins primarily involved in facilitating the transport of water, glycerol, and other small solutes across cellular membranes [4]. AQP7 is highly expressed in adipose tissue, kidney, and testis, playing a significant role in glycerol metabolism and osmoregulation. In adipocytes, AQP7 enables the efflux of glycerol [5], a critical process in lipid metabolism and energy homeostasis. Dysregulation of AQP7 expression has been linked to metabolic disorders, including obesity and insulin resistance. Its glycerol channel activity also contributes to spermatogenesis in the testis and renal glycerol handling in the kidney [6,4].
Potential binding sites on the surface of an aquaporin receptor (PDB ID: 8C9H) were predicted. Site-oriented and ligand-oriented dockings were applied. Site 1 (SiteScore = 1.065) was selected for a standard precision ligand docking against the Life ChemicalsHTS Compound Collection (Figure 1). Moreover, the docking site was also mapped and utilized based on the ligand interaction shown in the structure of 8C9H. The results of the two approaches were combined into a final set of 9,554 compounds that showed a docking score of less than -8.99. Subsequent dissimilarity selection reduced the initial selection by half.
Thereby, over 900 top-scored screening compounds were selected for this nAChR Targeted Screening Set. All presented compounds correspond to QikProp parameters and descriptors and have a docking score value less than -10.
Key features
- Method: high-throughput virtual screening (docking)
- X-Ray data used: 8C9H
- Constraints: metal coordination
- Protein rotatable groups allowed: yes
- Filters used: PAINS, toxic, reactive
- Number of compounds selected: 3,979
Figure 3. Structure of AQP7 with potential inhibitor F5834-3090 positioned in the protein pore.
Figure 4. Binding mechanism of AQP7 with potential inhibitors, illustrated by protein-ligand interaction with F5834-3090.
References
- Su, Wen et al. “Aquaporins in the kidney: physiology and pathophysiology.” American journal of physiology. Renal physiology vol. 318,1 (2020): F193-F203. doi:10.1152/ajprenal.00304.2019.
- 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
- Zhang, Li et al. “The structural basis for glycerol permeation by human AQP7.” Science bulletin vol. 66,15 (2021): 1550-1558. doi:10.1016/j.scib.2020.12.006
- da Silva, Inês V, and Graça Soveral. “Aquaporins in Obesity.” Advances in experimental medicine and biology vol. 1398 (2023): 289-302. doi:10.1007/978-981-19-7415-1_20
- Ribeiro, João C et al. “Aquaporin-7-Mediated Glycerol Permeability Is Linked to Human Sperm Motility in Asthenozoospermia and during Sperm Capacitation.” Cells vol. 12,15 2003. 5 Aug. 2023, doi:10.3390/cells12152003