多种药理学翻译为物种与遗传学距离:对有机离子载体聚的功能,生物信息和结构研究
Katja Stefan1, Vigneshwaran Namasivayam2, Mst Tazmin Akhter3
1University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck Institute of Experimental Dermatology, Medicinal Chemistry and Systems Polypharmacology, Ratzeburger Allee 160, 23538 Lübeck, Germany; University of Oslo and Oslo University Hospital, Department of Pathology, Rikshospitalet, Sognsvannsveien 20, 0372 Oslo, Norway.
多目标ATP结合盒 (Pan-ABC) 载体调节器有效抑制斑马鱼有机离子载体聚 (drOatp1d1). 这表明在多种膜载体中保留了结合点,有助于药物开发.
科学领域:
- 生物化学 生物化学
- 药理学 药理学是指药理学的学科.
- 结构生物学 结构生物学
背景情况:
- 膜载体是关键的药物点,但许多仍然是不可用药的.
- "多目标结合点"的概念建议在各种蛋白质中保留结构动机.
- 斑马鱼 (Danio rerio) 模型对于体内药物开发研究至关重要.
研究的目的:
- 功能性地评估多目标ATP结合盒 (pan-ABC) 载体调节器与斑马鱼有机离子载体聚 (drOatp1d1) 相比.
- 研究膜传送器中保留结合点的潜力.
- 评估这些调节器在斑马鱼和人类系统之间的转化效用.
主要方法:
- 针对drOatp1d1.1,对23个泛ABC传输器调制器进行功能评估.
- 观察到的效应与已知的人类有机离子载体多 (OATPs) 的比较.
- 使用冷电子显微镜 (cryo-EM) 分析OATP1B1.1.的潜在结合部位相互作用的结构.
主要成果:
- 87.0%的测试化合物抑制了drOatp1d1的运输.
- 对drOatp1d1的抑制作用与人类OATP1A2,OATP1B1,OATP1B3和OATP2B1.1所观察到的效果相似.
- 强大的抑制剂可能与drOatp1d1内的保留位置结合,从OATP1B1结构中预测.
- 普兰卢卡斯特对人类OATP的活性被其drOatp1d1活性准确地预测出来.
- 调节器还对其他斑马鱼和非斑马鱼膜载体表现出活性.
结论:
- 这项研究支持了膜传送器中保存的结构动图的存在,由泛ABC调节器在drOatp1d1.1上的活性证明了这一点.
- 这些发现突显了使用斑马鱼模型和保存结合点向调节器用于药物发现的潜力.
- 鉴定到的调节器作为一种有价值的工具,可以通过保存的结构动机来解决膜载体和潜在的其他蛋白质家族的不耐药性问题.
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