大图书馆对接识别了感应受体的正调节器
Fangyu Liu1, Cheng-Guo Wu2, Chia-Ling Tu3
1Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
Science (New York, N.Y.)
|September 19, 2024
概括
通过大规模分子对接,发现了感受受体 (CaSR) 的新阳性异质调节剂 (PAM). 这些强大的CaSR PAM可用于治疗甲状腺功能障碍而不会导致低血症.
科学领域:
- 生物化学
- 药理学
- 结构生物学
背景情况:
- 阳性基调节剂 (PAMs) 向感应受体 (CaSR) 抑制副甲状腺激素 (PTH) 分泌,用于治疗副甲状腺症.
- 现有的CaSR PAM可能会导致低血和心律失常等不良反应,因此需要开发更好的治疗方法.
研究的目的:
- 通过大规模的分子对接和基于结构的优化来识别新的,更强大的和更安全的CaSR PAM.
- 在临床前模型中评估新发现的CaSR PAM的疗效和安全性.
主要方法:
- 使用大规模分子对接,对抗CaSR结构的270万和12亿个分子.
- 进行基于结构的优化,将化合物精制成纳米级药物候选物.
- 使用ex vivo器官测定和in vivo小鼠模型评估化合物的功效和有效性,包括PTH水平和血清度测量.
- 使用冷电子显微镜确定CaSR-PAM复合物的高分辨率结构.
主要成果:
- 与百万分子库相比, 10 亿分子对接方法的成功率是 2.7 倍, PAM 效果高达 37 倍.
- 基于结构的优化导致具有纳米分子功能的化合物.
- 一个优化的PAM在ex vivo测试中显示出比cinacalcet大100倍的效果,并且有效地降低了小鼠的PTH水平,而不会引起低血症.
- 冷电磁结构显示,已识别的PAM稳定了接近完全激活状态的CaSR构造.
结论:
- 大规模的分子对接是发现高强度的CaSR PAM的有效策略.
- 与现有药物相比,新型CaSR PAM具有更高的功效和更好的安全性,为甲状腺功能增强提供了有前途的治疗途径.
- 结构洞察力阐明了这些PAM实现增强CaSR激活的机制.
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