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首页> 外文期刊>Journal of cellular biochemistry. >Mechanistic and structural insight into promiscuity based metabolism of cardiac drug digoxin by gut microbial enzyme
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Mechanistic and structural insight into promiscuity based metabolism of cardiac drug digoxin by gut microbial enzyme

机译：肠道微生物酶对心脏药物高辛的滥交组成的机械与结构洞察

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Abstract The recent advances in microbiome studies have revealed the role of gut microbiota in altering the pharmacological properties of oral drugs, which contributes to patient‐response variation and undesired effect of the drug molecule. These studies are essential to guide us for achieving the desired efficacy and pharmacological activity of the existing drug molecule or for discovering novel and more effective therapeutics. However, one of the main limitations is the lack of atomistic details on the binding and metabolism of these drug molecules by gut‐microbial enzymes. Therefore, in this study, for a well‐known and important FDA‐approved cardiac glycoside drug, digoxin, we report the atomistic details and energy economics for its binding and metabolism by the Cgr2 protein of Eggerthella lenta DSM 2243 . It was observed that the binding pocket of digoxin to Cgr2 primarily involved the negatively charged polar amino acids and a few non‐polar hydrophobic residues. The drug digoxin was found to bind Cgr2 at the same binding site as that of fumarate, which is the proposed natural substrate. However, digoxin showed a much lower binding energy (17.75?±?2?Kcal?mol ?1 ) than the binding energy (42.17?±?2?Kcal?mol ?1 ) of fumarate. This study provides mechanistic insights into the structural and promiscuity‐based metabolism of widely used cardiac drug digoxin and presents a methodology, which could be useful to confirm the promiscuity‐based metabolism of other orally administrated drugs by gut microbial enzymes and also help in designing strategies for improving the efficacy of the drugs.
机译：摘要微生物群研究的最新进展揭示了肠道微生物群在改变口服药物药理特性中的作用，这有助于患者反应的变化和药物分子的不良效应。这些研究对于指导我们实现现有药物分子的预期疗效和药理活性，或发现新的更有效的治疗方法至关重要。然而，其中一个主要的限制是缺乏关于这些药物分子通过肠道微生物酶结合和代谢的原子细节。因此，在本研究中，对于一种众所周知且重要的FDA批准的强心苷药物地高辛，我们报告了其与Eggerthella lenta DSM 2243的Cgr2蛋白结合和代谢的原子细节和能量经济学。据观察，地高辛与Cgr2的结合囊主要涉及带负电的极性氨基酸和一些非极性疏水残基。研究发现，地高辛与延胡索酸的Cgr2结合位点相同，延胡索酸是天然底物。然而，地高辛的结合能（17.75±2 Kcal？mol？1）远低于富马酸的结合能（42.17±2 Kcal？mol？1）。这项研究为广泛使用的心脏药物地高辛的结构和滥交代谢提供了机制上的见解，并提出了一种方法，该方法有助于通过肠道微生物酶确认其他口服药物的滥交代谢，也有助于设计提高药物疗效的策略。

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