Identification of effective inhibitors against epsilon toxin (ETX) of Clostridium perfringens: Virtual screening and molecular dynamics simulation.

In spite of the potential for toxicity in humans, no therapeutics are approved against Epsilon toxin (ETX) for human use. Therefore, finding effective inhibitors for this toxin has garnered a lot of attention. In this regard, we performed an in silico study to find effective inhibitors against this toxin. To this end, the structure of ETX and an experimentally approved ETX inhibitor were prepared and docked as a control interaction and used for the determination of the binding site. An approved library of small molecules was obtained from the DrugBank database and prepared for virtual screening via size filtering and the addition of conformations. The top five molecules with the highest binding energy were used to draw their 2D interaction plots against ETX. A 100 ns MD simulation was performed on the Antrafenine-ETX complex as the best result of the screening stage in comparison to the control complex. The obtained results showed that among the 3849 molecules (which were analyzed by virtual screening), Cefotiam, Antrafenine, Ferric Derisomaltose, Mupirocin, and Salmeterol had the highest binding energies (binding energies respectively calculated to be -5.6, -5.8, -4.9, -4.9, and -4.6 kcal/mol). The 2D interaction plots also showed that the screened molecules had stronger interacting bonds with the ETX protein. MD simulations showed that the Antrafenine-ETX complex has a similar RMSD plot to the control complex, while its RMSF, hydrogen bond, and GR plots show better results for the Antrafenine-ETX complex. In light of these results, Antrafenine could be the best choice for ETX inhibition regarding strength, while based on the route of administration and drug applications, Cefotiam could also be considered for ETX inhibition. It seems that despite the promising results of the performed in silico studies, further empirical pieces of evidence would strengthen these conclusions in future studies.