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Aquaporins are integral membrane proteins that facilitate the transport of water in and out of cells in response to osmotic gradient. Aquaporins are unique in their selective permeability, which allows the passage of water while blocking other small molecules and protons. AQps are essential for maintaining water balance within cells and across tissues, and function by allowing water molecules to pass through their pores in a single file. The structure of aquaporins typically includes six membrane-spanning α-helices with both N- and C-termini located intracellularly. The pores are formed by two highly conserved asparagine-proline-alanine (NPA) motifs, which are critical for selective water transport. Each monomer unit of aquaporins is approximately 30 kDa and consists of six transmembrane alpha helices (M1, M2, M4-M8), two half helices (M3 and M7), and connecting loops.






AQP2 is expressed on the apical membrane of the collecting ducts in renal cells. The expression of AQP2 is mediated by the vasopressin hormone secreted from the brain. In the kidneys, aquaporins are involved in the reabsorption of water from pre-urine, which is crucial for maintaining fluid balance in the body, mutations or inhibition of AQP2 is lead to a condition called nephrogenic diabetic insipidus. AQP4 channels have been identified in several diseases and pathological conditions, such as edema, ischemia, Alzheimer’s disease, and Sjögren's syndrome. Aquaporin 5 (AQP5) is essential for maintaining corneal and lens transparency and its dysfunction is associated with various ocular diseases. Furthermore, knockout mouse experiments have reported the involvement of aquaporins in epithelial fluid secretion, brain edema, adipocyte metabolism, and cell migration, indicating their potential therapeutic applications through channel modulation. The structure-function relationship of aquaporins is complex, and mutations in specific regions can drastically alter their water permeability without affecting their expression on the plasma membrane. The potential of aquaporins as therapeutic targets is significant given their involvement in diseases such as nephrogenic diabetes insipidus, Sjögren's syndrome, and heart failure. However, the development of aquaporin inhibitors has been challenging because of the presence of multiple cells and organs and the structural constraints of the aquaporin molecule.  






It is challenging to design aquaporin inhibitors that can selectively target specific cells and organs, while minimizing their impact on other parts of the body. Approaches to drug design are being explored to address the structural constraints of aquaporin molecules and to improve the efficacy of inhibitors.  To overcome these challenges, alternative approaches to target aquaporin function are needed, such as the use of small-molecule inhibitors to disrupt the channel activity. To identify the specific structural features that are critical for aquaporin function, we aimed to design more effective small-molecule inhibitors that can selectively target proteins in a variety of cellular contexts. Inhibition of AQP2 and AQP4 is associated with conditions such as NDI and cerebral edema. The blocking of these channels using potential mycotoxins, such as T-2 toxin, citrinin, and ochratoxin, shows the potential role of histidine residues, apart from arginine, in the pore region. These small molecules partially inhibit expression and alter the function of the channel through pore blocking and steric hindrance in the pore region. Residue conservation and residue network analysis of the amino acids of the channel also showed conservation of these residues in the pore region. Furthermore, the expression of AQP4 in astrocytes reduces amyloid peptide aggregation by maintaining the less toxic alpha helices of the peptide, which helps in the clearance of the peptide. Our research focused on understanding aquaporins and their roles in various diseases, small-molecule inhibitor design, and pathophysiological conditions. 

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