In silico identification of flavonoid inhibitors targeting cholera toxin from Vibrio cholerae: Molecular docking, ADMET profiling, and molecular dynamics simulation.

Abstract

An integrated computational strategy was used to identify potential inhibitors of the NAD (+)-arginine ADP-ribosyl transferase of cholera toxin. The target protein structure was obtained from the UniProt database and validated using PROCHECK. The potential binding pockets were predicted using DeepSite. A total of 50 flavonoids were screened using structure based virtual screening (VS), of which Kaempferol (-9.1 kcal/mol) and Taxifolin (-8.9 kcal/mol) were identified as potential inhibitors. Molecular interaction studies indicated that kaempferol had a substantially larger interaction network (greater number of hydrogen bonds, pi-pi interactions and hydrophobic interactions) than taxifolin. ADMET and toxicity profiling for each compound indicated that both compounds had favorable drug-like properties including high GI absorption, low BBB penetrability, and acceptable toxicity profiles. 100 ns molecular dynamics analyses showed stable binding for both ligands. Kaempferol had faster equilibration times, less flexible protein, and less solvent exposure than taxifolin. Additionally, MM-GBSA binding free energy analyses further corroborate the binding affinity of kaempferol/taxifolin was stronger (-36.28 vs -30.62 Kcal/mol binding affinity). Collectively, these findings show that kaempferol is a viable lead compound for cholera toxin suppression and serve as the foundation for future antitoxin medication development and experimental validation.