Ricin is a ribosome-inactivating protein (RIP type 2) consisting of two subunits, ricin toxin A (RTA) and ricin toxin B (RTB). Because of its cytotoxicity, ricin has worried world authorities for its potential use as a chemical weapon; therefore, its inhibition is of great biotechnological interest. RTA is the target for inhibitor synthesis, and pterin derivatives are promising candidates to inhibit it. In this study, we used a combination of the molecular docking approach and fast steered molecular dynamics (SMD) to assess the correlation between nonequilibrium work, ⟨W⟩, and the IC₅₀ for six RTA inhibitors. The results showed that molecular docking is a powerful tool to predict good bioactive poses of RTA inhibitors, and ⟨W⟩ presented a strong correlation with IC₅₀ (R² = 0.961). Such a profile ranked the RTA inhibitors better than the molecular docking approach. Therefore, the combination of docking and fast SMD simulation was shown to be a promising tool to distinguish RTA-active inhibitors from inactive ones and could be used as postdocking filtering approach.

中文翻译：

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通过分子对接和非平衡工作确定蓖麻毒素A抑制剂的相对结合亲和力

蓖麻毒素是一种核糖体失活蛋白（RIP 2型），由两个亚基，蓖麻毒蛋白毒素A（RTA）和蓖麻毒蛋白毒素B（RTB）组成。由于蓖麻毒素具有细胞毒性，因此令世界当局担心其可能用作化学武器。因此，其抑制具有重要的生物技术意义。RTA是抑制剂合成的目标，而蝶呤衍生物有望抑制它。在这项研究中，我们使用了分子对接方法的组合，并且快速转向分子动力学（SMD），以评估非平衡工作之间的相关性，⟨ W¯¯ ⟩，并且IC ₅₀为6 RTA抑制剂。结果表明，分子对接是预测RTA抑制剂的良好生物活性带来了强大的工具，并⟨ w ^⟩与IC ₅₀有很强的相关性（R ² = 0.961）。这样的特征使RTA抑制剂比分子对接方法更好。因此，对接和快速SMD模拟的结合被证明是区分RTA活性抑制剂和非活性抑制剂的有前途的工具，可以用作停靠后过滤方法。