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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：摘要近期微生物组研究的进展揭示了肠道微生物群在改变口腔药物的药理性质方面的作用，这有助于患者 - 响应变异和药物分子的不期望的作用。这些研究对于指导我们实现现有药物分子的所需疗效和药理活性或用于发现新颖和更有效的治疗方法是必不可少的。然而，主要限制之一是通过肠 - 微生物酶缺乏这些药物分子的结合和代谢的原子细节。因此，在本研究中，对于众所周知和重要的FDA批准的心脏糖苷药物，Digoxin，我们通过Eggerthella Lenta DSM 2243的CGR2蛋白报告了其结合和代谢的原子细节和能量经济学。观察到Digoxin的结合袋对CGR2主要涉及带负电的极性氨基酸和一些非极性疏水性残基。发现药物高辛将CGR2与富马酸盐的结合位点结合，这是所提出的天然基质。然而，Digoxin显示出比结合能量（42.17→±2？kcal？摩尔·Δ1）的结合能量低得多本研究提供了进入广泛使用的心脏药物高辛的结构和滥交的基础代谢的机械洞察，并提出了一种方法论，可用于通过肠道微生物酶确认其他口服给药的滥交性的基于滥用的代谢以及还有助于设计策略提高药物的疗效。

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