Aquaporins, also called water channels, are channel proteins from a larger family of major intrinsic proteins that form pores in the membrane of biological cells, mainly facilitating transport of water between cells ^[1]. Aquaporins (AQPs) are integral membrane proteins and found in all living organisms from bacteria to human. AQPs mainly involved in the transmembrane diffusion of water as well as various small solutes in a bidirectional manner are widely distributed in various human tissues. Human contains 13 AQPs (AQP0–AQP12) which are divided into three sub-classes namely orthodox aquaporin (AQP0, 1, 2, 4, 5, 6, and 8), aquaglyceroporin (AQP3, 7, 9, and 10) and super or unorthodox aquaporin (AQP11 and 12) based on their pore selectivity ^[2].

Although the amino acid sequences differ substantially, the structure of AQPs is highly conserved having a common tetrameric arrangement; each subunit behaves as a functional channel ^[3]. However, a fifth pore is formed in the center of the tetramer. Each monomer is constituted of six transmembrane (TM) α-helices (H1–H6) with five connecting loops (loops LA–LE) and cytoplasmic N- and C-termini and form an individual pore that specifies the transport activity. There are two main constrictions in the channel. The first constriction is formed by two highly conserved Asn-Pro-Ala (NPA) motifs on loops B and E that is involved in proton exclusion ^[4]. Both NPA motifs protrude into the membrane from opposite side and form the seventh pseudo TM helix. The second constriction, called the aromatic/arginine (ar/R) selectivity filter, is formed by four residues from helix H2 and H5, and loop E (LE1 and LE2) ^[5]. Substitutions at this ar/R selectivity filter are thought to determine the broad spectrum of substrate conductance ^[6]. While all AQPs share the same structural core architecture, there are some distinct structural variations in loops and the N- and C-termini suggesting their functional and/or regulatory roles ^[7].

There are three classes of AQP inhibitors: metal-related inhibitors, quaternary ammonium salts, and small molecule inhibitors which are further divided into four parts: sulfanilamide analogies, TGN-020, antiepileptic drugs, and others. It has been suggested that although they showed inhibition effects on AQP1, AQP3, AQP4, AQP7, or AQP9 in some researches, none of them could be asserted as AQP inhibitors to some extent ^[8].

Auphen is the most active on AQP3 (IC₅₀: 0.8±0.08 µM in hRBC). Interestingly, the compound poorly affects the water permeability of AQP1. The mechanism of gold inhibition is related to the ability of Au(III) to interact with sulphydryls groups of proteins such as the thiolates of cysteine residues ^[9].

AQP1 ion channel blocker AqB011 and water channel blocker Bacopaside II ^[11]. hAQP1 blockers and bind at the extracellular entrance of the channel, close to the ar/R selectivity filter. Furthermore, mutagenesis studies showed that Lys36, which is not conserved among the hAQP family ^[12].

Different from another channel, AQP6 is activated by Hg^{2+ [10]}.