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首页> 外文期刊>RSC Advances >Drug-likeness of linear pentamidine analogues and their impact on the hERG K+ channel - correlation with structural features
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Drug-likeness of linear pentamidine analogues and their impact on the hERG K+ channel - correlation with structural features

机译：线性戊脒类似物的药物肖像及其对Herg K +通道的影响 - 与结构特征相关

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This work presents drug-likeness and the cardiotoxicity profiles of six potent pentamidine analogs 1-6 and three new compounds 7-9 as chemotherapeutics for therapy of Pneumocystis jiroveci pneumonia. A combination of experimental and computational approaches was used in the cardiotoxicity examination. The hERG trafficking and functionality of the hERG currents were tested by western blot analyses, immunofluorescent staining procedures, and patch-clamp electrophysiological assays. Cardiotoxicity combined with blocking the hERG K+ channel was predicted, and then simulated by docking to the CSM-TM model 732 protein. Location of pentamidines in the proximity of Leu622, Thr623, Ser649, Tyr652, Ala653, and Phe656, and the high energies of interactions were in accordance with probable blocking of the hERG channel. However, in the biochemical experiments, no significant changes in I-hERG densities and a minor effect on hERG maturation were observed. Predicted metabolic transformation of pentamidines with S atoms in the aliphatic linker leads to oxidation of one S atom, but those with the phenyl sulfanilide moiety can be oxidized to chinones. The tested pentamidines characterized by the presence of sulfur atoms or sulfanilide groups, have favorable drug-likeness parameters and are promising lead structures in the development of new potent chemotherapeutics against PJP.
机译：这项工作呈现出六种有效的五聚脒类似物1-6和三种新化合物7-9作为肺炎治疗肺炎治疗的药物似的特性和血管毒性曲线。在心脏毒性检查中使用了实验和计算方法的组合。通过Western印迹分析，免疫荧光染色程序和贴片电生理测定来测试HERG贩运和HERG电流的功能。预测心脏毒性与阻断HERG K +通道进行预测，然后通过对接到CSM-TM型732蛋白来模拟。五脒的位置在Leu622，Thr623，Ser649，Tyr652，ALA653和PHE656附近，以及互及的高能量均按照Herg通道的可能阻断。然而，在生化实验中，观察到I-HERG密度的显着变化和对HERG成熟的微小影响。预测脂族接头中具有S原子的五脒的代谢转化导致氧化物原子，但是苯基磺硅烷部分的那些可以氧化成Chlones。通过硫原子或亚磺酰基存在的存在的测试的五聚脒具有良好的药物肖像参数，并且是在对PJP的新有效化学治疗方法开发中具有有前途的铅结构。

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    《RSC Advances》 |2019年第66期|共17页
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  • 正文语种 eng
  • 中图分类 化学;
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