Virtual Screening for the Discovery of Microbiome β-Glucuronidase Inhibitors to Alleviate Cancer Drug Toxicity
| العنوان: | Virtual Screening for the Discovery of Microbiome β-Glucuronidase Inhibitors to Alleviate Cancer Drug Toxicity |
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| المؤلفون: | Anup P. Challa, Xin Hu, Ya-Qin Zhang, Jeffrey Hymes, Bret D. Wallace, Surendra Karavadhi, Hongmao Sun, Samarjit Patnaik, Matthew D. Hall, Min Shen |
| المصدر: | J Chem Inf Model |
| بيانات النشر: | American Chemical Society (ACS), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Drug-Related Side Effects and Adverse Reactions, Microbiota, Neoplasms, General Chemical Engineering, Humans, Antineoplastic Agents, General Chemistry, Enzyme Inhibitors, Library and Information Sciences, Article, Early Detection of Cancer, Glycoproteins, Computer Science Applications |
| الوصف: | Despite the potency of most first-line anti-cancer drugs, non-adherence to these drug regimens remains high and is attributable to the prevalence of “off-target” drug effects that result in serious adverse events (SAEs) like hair loss, nausea, vomiting, and diarrhea. Some anti-cancer drugs are converted by liver uridine 5’-diphospho-glucuronosyltransferases through homeostatic host metabolism to form drug-glucuronide conjugates. These sugar-conjugated metabolites are generally inactive and can be safely excreted via the biliary system into the gastrointestinal tract. However, β-glucuronidase (βGUS) enzymes expressed by commensal gut bacteria can remove the glucuronic acid moiety, producing the reactivated drug and triggering dose-limiting side effects. Small-molecule βGUS inhibitors may reduce this drug-induced gut toxicity, allowing patients to complete their full course of treatment. Herein, we report the discovery of novel chemical series of βGUS inhibitors by structure-based virtual high-throughput screening (vHTS). We developed homology models for βGUS and applied them to large-scale vHTS against nearly 400,000 compounds within the chemical libraries of the National Center for Advancing Translational Sciences at the National Institutes of Health. From the vHTS results, we cherrypicked 291 compounds via a multifactor prioritization procedure, providing 69 diverse compounds that exhibited positive inhibitory activity in a follow-up βGUS biochemical assay in vitro. Our findings correspond to a hit rate of 24% and could inform the successful downstream development of a therapeutic adjunct that targets the human microbiome to prevent SAEs associated with first-line, standard-of-care anti-cancer drugs. |
| تدمد: | 1549-960X 1549-9596 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8f1eb78c4aab121875378e120b648365 https://doi.org/10.1021/acs.jcim.1c01414 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....8f1eb78c4aab121875378e120b648365 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 1549960X 15499596 |
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