Discovery of potential phytochemicals as inhibitors of TcdB, a major virulence factors of Clostridioides difficile

Clostridioides difficile is a gram-positive bacterium which is associated with different gastrointestinal related infections, and the numbers of cases related to it are continuously increasing in the past few years. Owing to high prevalence and development of resistance towards available antibiotics, it is required to develop new therapeutics to combat C. difficile infection. The current study was aimed to identify novel phytochemicals that could bind and inhibits the TcdB, an exotoxin which is required for the pathogenesis of bacteria, and hence can be considered as the future drug candidates against C. difficile. ∼2500 therapeutically important phyto-compounds were docked against the active sites of TcdB protein by using AutoDock-Vina software. The interactions between the ligands and the binding site of the top five docked complexes, based on the docking scores, were further elucidated by Molecular Dynamics Simulations of 500 ns, Molecular Mechanics Energies combined with the Poisson–Boltzmann and Surface Area (MMPBSA) or Generalized Born and Surface Area (MMGBSA), and WaterSwap Analysis. Findings of molecular docking suggested that natural compounds A183, A704, A1528, A2083, and A2129 with distinct chemical scaffolds are best docked in the binding site of TcdB and their bonding remained stable throughout the simulation studies of 500 ns. Compounds A2129 and A704 can be considered as prospective drug candidates against Clostridioides difficile, however, further wet lab experiments are needed to confirm our study. Communicated by Ramaswamy H. Sarma.