Chloride channels are a functionally and structurally diverse group of anion selective channels involved in processes including the regulation of the excitability of neurones, skeletal, cardiac and smooth muscle, cell volume regulation, transepithelial salt transport, the acidification of internal and extracellular compartments, the cell cycle and apoptosis ^[1]. Currently, the well characterised chloride channels can be classified as certain members of the voltage-sensitive ClC subfamily, calcium-activated channels (CaCC), high (maxi) conductance channels, the cystic fibrosis transmembrane conductance regulator (CFTR) and Volume-regulated anion channels (VRACs) ^[2]. In addition to some intracellular chloride channels that are not considered here, plasma membrane channels other than those listed have been functionally described. Many cells and tissues contain outwardly rectifying chloride channels (ORCC) that may correspond to VRAC active under isotonic conditions.

There are some anothor chloride channels, such as cyclic AMP-activated Cl^-channel ^[3], cyclic GMP-activated Cl^-channel ^[4], and proton-activated, outwardly rectifying anion channel has also been described ^[5].

The AK-42 inhibitor is located above the Sext site and blocks the Cl⁻ channel. The hydrophobic pocket was formed by M460, F252, F459, F463, F306, and L397. Moreover, the AK-42 heterocycle also had hydrophobic interactions with I112 and L116 ^[6].

The inhibitors showed a very consistent binding conformation: the aromatic ring on the carbonyl side of the amide bond was embedded in the hydrophobic loop between α7 and α8, the carboxylic acid kept towards K767. As previously reported, α6 and the calcium-binding region produced large conformational changes during Ca²⁺ induced ANO1 activation, thereby compounds binding to this region(N767, E728, A723, E680, F679, F722, K767) might be effective to inhibit ANO1 ^[7]. TMEM16A-CaCC involves voltage-dependent occupancy of calcium and anion binding site(s) within the membrane electric field as well as a voltage-dependent conformational change intrinsic to the channel protein. These gating modalities all critically depend on the sixth transmembrane segment(I637,G640, Q645) ^[8].

Serine 537 of ClC-1 as a residue that largely determines its higher sensitivity for 9-AC and clofibrates ^[9].

Open-channel block of VRAC by calixarenes that also depends on the protonation of the binding site within the pore ^[12].

NFA inhibited native Cl with an IC₅₀ of 42 μM and blocked CLC-1 by interacting with an intracellular binding site ^[13].

Using a combination of cryo‐electron microscopy, electrophysiology, and autocorrelation analysis to show that agonist efficacy in the ligand‐gated channel TMEM16A is dictated by the conformation of the pore‐lining helix α6 around the Ca²⁺ binding site. The closure of the binding site, which involves the formation of a π‐helix below a hinge region in α6, appears to be coupled to the opening of the inner pore gate, thereby governing the channel's open probability and conductance. Our results provide a mechanism for agonist binding and efficacy and a structural basis for the design of potentiators and partial agonists in the TMEM16 family ^[10]. Niclosamide is predicted to have strong interactions with R605 and F601 located at the extracellular end of the TM5. The sidechains of these residues face towards the dimer interface and away from the ion permeation pathway. The NH2 group of R605 makes salt bridge contacts with the carboxy oxygen and hydrogen bonds with the carbonyl oxygen of the niclosamide hydroxybenamide moiety. F601 makes a pi-pi stack with the hydroxybenzamide ring and F781 on TM 9 makes a pi-pi stack with the nitrophenyl group.^[11].

BEST1 is a chloride channel that is activated by calcium. Vaisey and Long demonstrate that ionic currents through BEST1 inactivate by an allosteric mechanism in which the binding of a C-terminal peptide to a surface-exposed receptor controls a physically distant inactivation gate within the pore ^[14].

oleic acid inhibits TMEM16A by an allosteric mechanism after the electric field drives oleic acid's charged moiety inside the pore ^[15]. Anthracene‐9‐carboxylic acid (A9C), an inhibitor of various chloride channel types, exhibits complex effects on native CaCCs and cloned TMEM16A channels providing both activation and inhibition. Extracellular A9C competed with extracellular Cl⁻, suggesting that A9C binds deep in the channel's pore to exert both inhibiting and activating effects ^[16].

VX-770 is a potentiator of the CFTR channel and an approved therapy for cystic fibrosis. Yeh et al. find that the apparent affinity of a new potentiator, GLPG1837, is state dependent and propose an allosteric modulation model to explain the potency and efficacy of CFTR potentiators ^[17].