Detection of Potential Phytochemicals against ctxAB Toxin to Combat Cholera

Vibrio cholerae is a gram-negative curved rod-shaped bacterium responsible for cholera, an intestinal infection characterized by severe acute watery diarrhea that can be fatal if untreated. The major virulence factor for Vibrio cholerae is cholera toxin (ctx), a potent toxin which has two subunits, A and B (ctxAB), that are crucial for the progression of the deadly disease. The B subunit is a pentavalent protein that binds to the intestinal mucosa to allow internalization of the A subunit to initiate rice-watery diarrhea. This study explored potential phytochemicals to inhibit the B subunit from binding to the host mucosa by examining their interaction with ctxB. Proteins encoded by the three genotypes of the ctxB gene (ctxB1, ctxB3, and ctxB7) present in the El Tor biotype strains of V. cholerae O1 responsible for the currently ongoing seventh cholera pandemic were targeted. Analysis of 52 phytochemicals obtained from PubChem identified a group of phytochemicals based on their binding affinity scores with the proteins of ctxB genotypes. Assessment of drug-likeliness and toxicity risk highlighted two phytochemicals, Limonin and Emodin, as the best potential candidates for inhibiting the mode of action of cholera toxin. Molecular dynamic (MD) simulation-based MM-PBSA analysis suggested these compounds stably interact with the receptors. Molecular docking and molecular dynamic simulations revealed that these phytochemicals might have potential to inhibit the cholera toxin function and reduce the severity of cholera. Author SummaryCholera toxin (ctx) subunits A and B (ctxAB) play a significant role in the disease, with the B subunit facilitating the binding of the toxin to the intestinal cells, and the A subunit entering the cells, resulting in the cellular changes that lead to watery diarrhea. To inhibit the B subunit of cholera toxin from binding host mucosa, we explored candidate phytochemicals instead of synthetic molecules as drug agents by examining their binding behavior with ctxB using a molecular docking approach. The molecular docking, molecular dynamic simulations, and toxicity analyses identified two phytochemical compounds that have the potential to inhibit the mechanism of cholera toxin.