Irinotecan (CPT-11) is a cytotoxic drug that has wide applicability and usage in cancer treatment. Despite its success, patients suffer dose-dependent diarrhea, limiting the drug's efficacy. No effective therapy is available for this unmet medical need. The bacterial β-glucuronidase (β-GUS) plays pivotal role in CPT-11-induced diarrhea (CID) via activating the non-toxic SN-38G to toxic SN-38 inside intestine. By using structural-based virtual screening, three old drugs (N-Desmethylclozapine, Aspartame, and Gemifloxacin) were firstly identified as selective bacterial β-GUS inhibitors. The IC50 values of the compounds in the enzyme-based and cell-based assays range from 0.0389 to 3.6040 and 0.0105 to 5.3730 μM, respectively. The compounds also showed good selectivity against mammalian β-GUS and no significant cytotoxicity in bacteria. Molecular docking and molecular dynamics simulations were performed to further investigate the binding modes of compounds with bacterial β-GUS. Binding free energy decomposition revealed that the compounds formed strong interactions with E413 in catalytic trail from primary monomer and F365' on the bacterial loop from the other monomer of bacterial β-GUS, explaining the selectivity against mammalian β-GUS. The old drugs identified here may be used as bacterial β-GUS inhibitors for CID or other bacterial β-GUS-related disorders.

中文翻译：

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通过基于结构的虚拟筛选和生物评估，将旧药鉴定为选择性细菌β-GUS抑制剂。

伊立替康（CPT-11）是一种细胞毒性药物，在癌症治疗中具有广泛的适用性和用途。尽管取得了成功，但患者仍会出现剂量依赖性腹泻，从而限制了该药的疗效。对于这种未满足的医疗需求，没有有效的治疗方法。细菌β-葡萄糖醛酸苷酶（β-GUS）通过将无毒SN-38G激活为肠道内的有毒SN-38，在CPT-11-诱导的腹泻（CID）中起关键作用。通过基于结构的虚拟筛选，首先鉴定了三种旧药物（N-去甲基氯氮平，阿斯巴甜和吉米沙星）作为选择性细菌性β-GUS抑制剂。在基于酶的分析和基于细胞的分析中，化合物的IC50值分别为0.0389至3.6040和0.0105至5.3730μM。该化合物还显示出对哺乳动物β-GUS的良好选择性，并且对细菌没有明显的细胞毒性。进行了分子对接和分子动力学模拟，以进一步研究化合物与细菌β-GUS的结合模式。结合自由能的分解表明，该化合物与E413在主要单体的催化痕迹中与E413形成了强烈的相互作用，并与细菌β-GUS的其他单体在细菌环上的F365'形成了强相互作用，从而说明了对哺乳动物β-GUS的选择性。此处鉴定的旧药物可用作CID或其他细菌性β-GUS相关疾病的细菌性β-GUS抑制剂。细菌β-GUS的其他单体在细菌环上的表达，说明了对哺乳动物β-GUS的选择性。此处鉴定的旧药物可用作CID或其他细菌性β-GUS相关疾病的细菌性β-GUS抑制剂。细菌β-GUS的其他单体在细菌环上的表达，说明了对哺乳动物β-GUS的选择性。此处鉴定的旧药物可用作CID或其他细菌性β-GUS相关疾病的细菌性β-GUS抑制剂。