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Computer-Guided Trypanocidal Activity of Natural Lactones Produced by Endophytic Fungus of Euphorbia umbellata
Chemistry & Biodiversity ( IF 2.3 ) Pub Date : 2021-08-17 , DOI: 10.1002/cbdv.202100493 Amanda Santos Gusmão 1 , Lucas Silva Abreu 2 , Josean Fechine Tavares 2 , Humberto Fonseca Freitas 3 , Samuel Pita 4 , Elda Santos 5 , Ivo Caldas 5 , André Alexandre Vieira 1 , Eliane Oliveira Silva 6
Chemistry & Biodiversity ( IF 2.3 ) Pub Date : 2021-08-17 , DOI: 10.1002/cbdv.202100493 Amanda Santos Gusmão 1 , Lucas Silva Abreu 2 , Josean Fechine Tavares 2 , Humberto Fonseca Freitas 3 , Samuel Pita 4 , Elda Santos 5 , Ivo Caldas 5 , André Alexandre Vieira 1 , Eliane Oliveira Silva 6
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Hundreds of millions of people worldwide are affected by Chagas’ disease caused by Trypanosoma cruzi. Since the current treatment lack efficacy, specificity, and suffers from several side-effects, novel therapeutics are mandatory. Natural products from endophytic fungi have been useful sources of lead compounds. In this study, three lactones isolated from an endophytic strain culture were in silico evaluated for rational guidance of their bioassay screening. All lactones displayed in vitro activity against T. cruzi epimastigote and trypomastigote forms. Notably, the IC50 values of (+)-phomolactone were lower than benznidazole (0.86 vs. 30.78 μM against epimastigotes and 0.41 vs. 4.88 μM against trypomastigotes). Target-based studies suggested that lactones displayed their trypanocidal activities due to T. cruzi glyceraldehyde-3-phosphate dehydrogenase (TcGAPDH) inhibition, and the binding free energy for all three TcGAPDH-lactone complexes suggested that (+)-phomolactone has a lower score value (−3.38), corroborating with IC50 assays. These results highlight the potential of these lactones for further anti-T. cruzi drug development.
中文翻译：
由大戟内生真菌产生的天然内酯的计算机引导的杀锥虫活性
全世界有数亿人受到由克氏锥虫引起的恰加斯病的影响。由于目前的治疗缺乏疗效、特异性，并且存在多种副作用，因此必须采用新的治疗方法。来自内生真菌的天然产物一直是先导化合物的有用来源。在这项研究中，从内生菌株培养物中分离出的三种内酯进行了计算机评估，以对其生物测定筛选进行合理指导。所有内酯都表现出针对T. cruzi 上鞭毛体和锥鞭毛体形式的体外活性。值得注意的是，IC 50(+)-phololactone 的值低于苯并硝唑（针对上鞭毛体为 0.86 对 30.78 μM，对锥鞭毛体为 0.41 对 4.88 μM）。基于靶标的研究表明，由于T. cruzi甘油醛-3-磷酸脱氢酶 ( Tc GAPDH) 抑制，内酯表现出它们的杀锥虫活性，并且所有三种Tc GAPDH-内酯复合物的结合自由能表明 (+)-phomolactone 具有较低的分值 (-3.38)，证实了 IC 50测定。这些结果突出了这些内酯在进一步抗克氏锥虫药物开发方面的潜力。
更新日期：2021-10-19
中文翻译：
由大戟内生真菌产生的天然内酯的计算机引导的杀锥虫活性
全世界有数亿人受到由克氏锥虫引起的恰加斯病的影响。由于目前的治疗缺乏疗效、特异性，并且存在多种副作用，因此必须采用新的治疗方法。来自内生真菌的天然产物一直是先导化合物的有用来源。在这项研究中，从内生菌株培养物中分离出的三种内酯进行了计算机评估，以对其生物测定筛选进行合理指导。所有内酯都表现出针对T. cruzi 上鞭毛体和锥鞭毛体形式的体外活性。值得注意的是，IC 50(+)-phololactone 的值低于苯并硝唑（针对上鞭毛体为 0.86 对 30.78 μM，对锥鞭毛体为 0.41 对 4.88 μM）。基于靶标的研究表明，由于T. cruzi甘油醛-3-磷酸脱氢酶 ( Tc GAPDH) 抑制，内酯表现出它们的杀锥虫活性，并且所有三种Tc GAPDH-内酯复合物的结合自由能表明 (+)-phomolactone 具有较低的分值 (-3.38)，证实了 IC 50测定。这些结果突出了这些内酯在进一步抗克氏锥虫药物开发方面的潜力。
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