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Discovery of a Histidine-Based Scaffold as an Inhibitor of Gut Microbial Choline Trimethylamine-Lyase.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-08-22 , DOI: 10.1002/cmdc.202000571 Moustafa Gabr 1 , Katarzyna Świderek 2
ChemMedChem ( IF 3.6 ) Pub Date : 2020-08-22 , DOI: 10.1002/cmdc.202000571 Moustafa Gabr 1 , Katarzyna Świderek 2
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Anaerobic choline metabolism by human gut microbiota to produce trimethylamine (TMA) has recently evolved as a potential therapeutic target because of its association with chronic kidney disease and increased cardiovascular risks. Limited examples of choline analogues have been reported as inhibitors of bacterial enzyme choline TMA‐lyase (CutC), a key enzyme regulating choline anaerobic metabolism. We used a new workflow to discover CutC inhibitors based on focused screening of a diversified library of small molecules for intestinal metabolic stability followed by in vitro CutC inhibitory assay. This workflow identified a histidine‐based scaffold as a CutC inhibitor with an IC50 value of 1.9±0.2 μM. Remarkably, the identified CutC inhibitor was able to reduce the production of TMA in whole‐cell assays using various bacterial strains as well as in complex gut microbiota environment. The improved efficiency of the new scaffold identified in this study in comparison to previously reported CutC inhibitors would enable optimization of potential leads for in vivo screening and clinical translation. Finally, docking studies and molecular‐dynamic simulations were used to predict putative interactions created between inhibitor and CutC.
中文翻译：
发现作为肠道微生物胆碱三甲胺裂解酶抑制剂的基于组氨酸的支架。
人类肠道微生物群产生三甲胺（TMA）的厌氧胆碱代谢最近已发展成为潜在的治疗靶点，因为它与慢性肾病和心血管风险增加有关。据报道，胆碱类似物的有限例子是细菌酶胆碱 TMA-裂解酶 (CutC) 的抑制剂，这是一种调节胆碱厌氧代谢的关键酶。我们使用新的工作流程来发现 CutC 抑制剂，该工作流程基于对肠道代谢稳定性的多样化小分子文库的集中筛选，然后进行体外CutC 抑制试验。该工作流程将基于组氨酸的支架鉴定为具有 IC 50的 CutC 抑制剂值 1.9±0.2 μM。值得注意的是，在使用各种细菌菌株以及复杂的肠道微生物群环境的全细胞分析中，鉴定出的 CutC 抑制剂能够减少 TMA 的产生。与之前报道的 CutC 抑制剂相比，本研究中确定的新支架的效率提高将能够优化体内筛选和临床转化的潜在线索。最后，对接研究和分子动力学模拟用于预测抑制剂和 CutC 之间产生的假定相互作用。
更新日期：2020-08-22
中文翻译：
发现作为肠道微生物胆碱三甲胺裂解酶抑制剂的基于组氨酸的支架。
人类肠道微生物群产生三甲胺（TMA）的厌氧胆碱代谢最近已发展成为潜在的治疗靶点，因为它与慢性肾病和心血管风险增加有关。据报道，胆碱类似物的有限例子是细菌酶胆碱 TMA-裂解酶 (CutC) 的抑制剂，这是一种调节胆碱厌氧代谢的关键酶。我们使用新的工作流程来发现 CutC 抑制剂，该工作流程基于对肠道代谢稳定性的多样化小分子文库的集中筛选，然后进行体外CutC 抑制试验。该工作流程将基于组氨酸的支架鉴定为具有 IC 50的 CutC 抑制剂值 1.9±0.2 μM。值得注意的是，在使用各种细菌菌株以及复杂的肠道微生物群环境的全细胞分析中，鉴定出的 CutC 抑制剂能够减少 TMA 的产生。与之前报道的 CutC 抑制剂相比，本研究中确定的新支架的效率提高将能够优化体内筛选和临床转化的潜在线索。最后，对接研究和分子动力学模拟用于预测抑制剂和 CutC 之间产生的假定相互作用。
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