Claudins, the major structural and functional components of epithelial tight junctions, control transport of ions and small molecules between individual epithelial cells. Specifically, claudin-2 and claudin-15 form paracellular cation selective channels in intestinal epithelia, which mediate the passive flow of sodium and water. Under physiological conditions, claudin-15 is critical for maintaining luminal sodium concentrations that drive nutrient absorption. In contrast, claudin-2 upregulation is pathophysiological, contributing to barrier dysfunction and diarrhea in conditions like inflammatory bowel disease (IBD), thereby positioning it as a potential therapeutic target. Using computational approaches, we identified candidate small molecules predicted to block claudin channels and evaluated their effects on transepithelial electrical resistance (TER) in Caco-2 BBE monolayers as well as MDCK I monolayers engineered to inducibly express claudin-2 or claudin-15. Through this strategy, we identified 114 claudin channel blockers, which exhibit various degrees of selectivity for claudin-2 or claudin-15 channels. The three top compounds were then studied using molecular dynamics simulations. We carried out all-atom molecular dynamics simulations, and key residues in channel-ligand interactions and the effect of the channel blockers on ion permeability were determined. Our results identify key structural determinants for claudin channel blockers that inhibit cation current and elucidate their distinct selectivity mechanisms for claudin-2 and claudin-15 channels.
Sajjadi et al. (Sun,) studied this question.
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