Javaherdehi Atefe Panahipoor, Hashemi Zahra Sadat, Khaleghi Sepideh, Bayazian Gholamreza
Department of Biotechnology, TeMS.C., Islamic Azad University, Tehran, Iran.
ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
Toxicon. 2025 Jun 16;264:108463. doi: 10.1016/j.toxicon.2025.108463.
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.
尽管ε毒素（ETX）对人类具有潜在毒性，但目前尚无获批用于人类的针对该毒素的治疗药物。因此，寻找该毒素的有效抑制剂备受关注。在这方面，我们进行了一项计算机模拟研究以寻找针对该毒素的有效抑制剂。为此，制备了ETX的结构以及一种经实验验证的ETX抑制剂，并将其作为对照相互作用进行对接，用于确定结合位点。从DrugBank数据库中获取了一个获批的小分子文库，并通过尺寸筛选和构象添加为虚拟筛选做准备。选取结合能最高的前五个分子绘制它们与ETX的二维相互作用图。与对照复合物相比，对筛选阶段最佳结果Antrafenine - ETX复合物进行了100 ns的分子动力学模拟。所得结果表明，在通过虚拟筛选分析的3849个分子中，头孢替安、安曲非宁、去铁胺麦芽糖铁、莫匹罗星和沙美特罗具有最高的结合能（结合能分别计算为-5.6、-5.8、-4.9、-4.9和-4.6 kcal/mol）。二维相互作用图还表明，筛选出的分子与ETX蛋白具有更强的相互作用键。分子动力学模拟表明，Antrafenine - ETX复合物的均方根偏差（RMSD）图与对照复合物相似，而其均方根波动（RMSF）、氢键和广义反应力（GR）图显示Antrafenine - ETX复合物的结果更好。鉴于这些结果，就强度而言，安曲非宁可能是抑制ETX的最佳选择，而基于给药途径和药物应用，头孢替安也可考虑用于抑制ETX。尽管所进行的计算机模拟研究取得了有前景的结果，但未来的研究中似乎仍需要更多实证证据来强化这些结论。
