新型 σ2R/TMEM97 配体的结构-亲和关系
Grant D Walby1, Qi Gu1, Hongfen Yang1
1Department of Chemistry, The University of Texas at Austin, Austin, TX 78712, United States.
Bioorganic chemistry
|March 3, 2024
概括
研究人员探索了新型的西格玛2受体 (σ2R) /跨膜蛋白97 (TMEM97) 调节器. 配体结构显著影响着对 σ2R/TMEM97 的结合亲和力和选择性,而不是对 σ1R.
科学领域:
- 药用化学 医学化学
- 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:
- 标识为跨膜蛋白97 (TMEM97) 的西格玛2受体 (σ2R) 是神经系统疾病的一个有前途的治疗点.
- 开发针对σ2的选择性调节器R/TMEM97对于推进神经科学疗法至关重要.
研究的目的:
- 为了合成和描述新型的佐沙素,索摩和甲扎平配体作为潜在的σ2R/TMEM97调节器.
- 评估这些新联体对 σ2R/TMEM97 和 σ1R 的结合亲和性和选择性.
主要方法:
- 基于已知的诺本佐摩基架构合成本佐佐沙,本佐摩和甲本扎平类型的类似物.
- 对 σ 2 R/TMEM97 和 σ 1 R 的结合亲和度 (Ki值) 的确定.
- 计算对接研究来预测配体-蛋白相互作用.
主要成果:
- 新型类似物对 σ2R/TMEM97 具有较低的结合亲和性和选择性,而与它们的诺本佐摩对应物相比.
- 对于 σ2R/TMEM97 对 σ1R 的联体选择性各不相同,而 EES-1686 衍生物具有最大的选择性.
- 接研究显示了连接体和σ2R/TMEM97残留物 (Asp29,Tyr150) 之间的保守的静电相互作用 (盐桥,子-π).
结论:
- 药用替代剂的空间定向对于 σ2R/TMEM97 带结合至关重要.
- 原子替代剂在实现 σ2R/TMEM97 与 σ1R 的选择性方面发挥着作用.
- 了解这些结构-活动关系可以指导设计更有效的向治疗方法.
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