Identification of plant-based inhibitors by molecular docking against catalytic glucosyltransferase domains of TcdA and TcdB toxins from clostridium difficile

As a frequent cause of colitis and nosocomial infections, Clostridium difficile continues to be an important pathogen of concern. To the authors' knowledge, no specific medication is available to counteract the effect of C. difficile toxins. This study aimed to identify the most potential antagonists for the two major toxins of C. difficile: TcdA and TcdB. A library of plant-derived compounds (N=8,858) was screened for toxin inhibitors using a series of computational methods. In standard-precision docking, the binding affinity for TcdA inhibitors was lower (-13.265 to-12.132 kcal/mol) than the control UDP-glucose (-9.62 kcal/mol). Similarly, the binding affinity for TcdB inhibitors was lower (-6.995 to-5.395 kcal/mol) than the control apigenin (-4.377 kcal/mol). The Gibbs free energy (Delta G) was also lower for TcdA inhibitors (-116.08 to -67.31 kcal/mol) and TcdB inhibitors (-59.88 to -35.06 kcal/mol) as compared to their respective controls (-13.82 and -41.26 kcal/mol, respectively). Based on interactions of these toxins and drug candidacy, the top 10 compounds for each target, providing higher binding affinities for TcdA and TcdB as compared to their positive controls, were identified. An evaluation of the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of these selected compounds suggests them to be good drug candidates against C. difficile toxins. Notably, one compound, TIP009928, was common in both selected inhibitor pools, and may be a good drug candidate against both TcdA and TcdB toxins. This finding is based on chemoinformatics and therefore requires validation with in vivo and in vitro experiments before these potential inhibitors could be considered as prospective therapeutics for C. difficile infections.

Automated summary

This study identified potential antagonists for the two major toxins of Clostridium difficile, TcdA and TcdB, from a library of plant-derived compounds through computational screening. The top 10 compounds for each target were found to have higher binding affinities compared to their positive controls, suggesting them to be good drug candidates against C. difficile toxins. Further validation with in vivo and in vitro experiments is needed before considering these potential inhibitors as prospective therapeutics.