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对于新的AQP4抑制剂:ORI-TRN-002

Michael Thormann¹, Nadine Traube¹, Nasser Yehia¹

¹Origenis GmbH, Am Klopferspitz 19A, 82152 Martinsried, Germany.

International journal of molecular sciences

|January 23, 2024

概括

研究人员发现了一种新化合物,ORI-TRN-002,它可以抑制水4 (AQP4) 水道. 这种新型的AQP4抑制剂对未来开发预防脑的疗法充满希望.

科学领域:

生物化学生物化学
神经科学是一个神经科学.
药理学药理学是指药理学的学科.

背景情况:

大脑水是一种危险的疾病,需要新的治疗方法来防止液体积聚,而不仅仅是降低压力.
水素4 (AQP4) 水道与大脑有关,使其成为治疗目标.
开发有选择性和有效的AQP4抑制剂面临着交付,毒性和持续作用方面的挑战.

研究的目的:

为了发现新型的Aquaporin 4 (AQP4) 抑制剂,用于潜在的脑 edem 治疗.
与现有的抑制剂相比,识别具有更好的特性 (如溶解性和减少蛋白质结合) 的化合物.
探索针对脑形成的新疗法策略.

主要方法:

密度函数理论 (DFT) 的计算确定了TGN-020的新稳定复合体.
基于新型 tautomer 模板的专有化合物的 COSMOsim-3D 虚拟选.
在体外评估候选ORI-TRN-002使用AQP4表达的Xenopus laevis卵细胞和高分辨率体积记录系统.

主要成果:

一个新的,热力学稳定的Tautomer的TGN-020被确定.
虚拟选确定了ORI-TRN-002,TGN-020的电子同类物,具有高溶解性和低蛋白结合性.
ORI-TRN-002显示出显著的水素4 (AQP4) 抑制,其IC50为2.9 ± 0.6μM.

结论:

ORI-TRN-002是一种新型和强大的水素4 (AQP4) 抑制剂.
与其他AQP4抑制剂相比,ORI-TRN-002具有优越的溶解性和药理动力学特性.
这些发现表明,ORI-TRN-002具有作为未来大脑的预防疗法的潜力.

关键词:

这是一种水素 (aquaporin).大脑胀脑胀水的透性是水的透性

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