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基于石英酸 (LCA) 的新型结构碎片的设计,合成,计算和生物评估

Jiangling Peng¹, Mingjie Fan², Kelly X Huang¹

¹Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.

Molecules (Basel, Switzerland)

|July 29, 2023

概括

研究人员通过修改石化酸 (LCA) 来开发出更多的爱水胆酸类型. 这些新化合物表现出类似的疗效和改善的Takeda G蛋白结合受体5 (TGR5) 相互作用,提供了一个有前途的治疗策略.

科学领域:

生物化学生物化学
药用化学医学化学
药理学药理学是指药理学的学科.

背景情况:

胆酸通路调节是代谢障碍和癌症的关键治疗标.
胆汁酸的疏水性限制了临床疗效,原因是异于目标效应.
石英酸 (LCA) 是一种具有治疗潜力的初级胆汁酸.

研究的目的:

设计具有增强水友性的新型石化酸 (LCA) 碎片.
评估这些新化合物的体外功效,疗效和安全性.
研究新型化合物与塔凯达G蛋白结合受体5 (TGR5) 的相互作用.

主要方法:

通过将极性氧原子引入侧链,对LCA进行化学修饰.
使用基于 luciferase 的记者测定和 MTS 细胞活力测定进行评估.
计算建模以分析与TGR5.5的键相互作用.

主要成果:

两种化合物 (1a-1b) 显示出改善的水友性,并且在体外耐受性很好.
化合物1a-1b保持了与LCA相似的强度和疗效.
计算分析显示,与LCA相比,化合物1a-1b和TGR5之间的增强结网络.
细胞活力在25μM以下的剂量下不受1a-1b化合物的影响.

结论:

这种新的策略成功地产生了更多的水友性LCA类似物.
化合物1a-1b代表了针对胆酸通路的治疗开发的有希望的候选者.
进一步的体内评估是有必要的,以探索这些化合物的生物活性.

关键词:

塔克达的G蛋白结合受体5 (TGR5) 是一种受体.胆汁酸胆汁酸胆汁酸水友性是一种水友性.基于 luciferase 的记者试验.代谢障碍代谢障碍代谢障碍结构活动关系 (SAR)

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