大型库对接确定了钙传感受体的正异构调节剂。

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2024-09-20 DOI:10.1126/science.ado1868

Fangyu Liu,Cheng-Guo Wu,Chia-Ling Tu,Isabella Glenn,Justin Meyerowitz,Anat Levit Kaplan,Jiankun Lyu,Zhiqiang Cheng,Olga O Tarkhanova,Yurii S Moroz,John J Irwin,Wenhan Chang,Brian K Shoichet,Georgios Skiniotis

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引用次数: 0

摘要

正性异位调节剂（PAM）药物能增强钙感受体（CaSR）的活化，抑制甲状旁腺激素（PTH）的分泌。遗憾的是，这些治疗甲状旁腺功能亢进的药物会诱发低钙血症和心律失常。为了寻找更好的调节剂，我们将 270 万和 12 亿个分子库与 CaSR 结构对接。十亿分子对接发现的 PAMs 的命中率比百万分子库高 2.7 倍，命中药效高达 37 倍。基于结构的优化产生了纳摩尔级的线索。在体内外器官试验中，其中一种 PAM 的效力是标准治疗药物西那卡西特的 100 倍，并能降低小鼠血清 PTH 水平，而不会出现 CaSR 药物特有的低钙血症。根据低温电子显微镜结构的测定，这里发现的 PAM 可促进 CaSR 的构象，这种构象比现有药物诱导的构象更接近活化状态。

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Large library docking identifies positive allosteric modulators of the calcium-sensing receptor.

Positive allosteric modulator (PAM) drugs enhance the activation of the calcium-sensing receptor (CaSR) and suppress parathyroid hormone (PTH) secretion. Unfortunately, these hyperparathyroidism-treating drugs can induce hypocalcemia and arrhythmias. Seeking improved modulators, we docked libraries of 2.7 million and 1.2 billion molecules against the CaSR structure. The billion-molecule docking found PAMs with a 2.7-fold higher hit rate than the million-molecule library, with hits up to 37-fold more potent. Structure-based optimization led to nanomolar leads. In ex vivo organ assays, one of these PAMs was 100-fold more potent than the standard of care, cinacalcet, and reduced serum PTH levels in mice without the hypocalcemia typical of CaSR drugs. As determined from cryo-electron microscopy structures, the PAMs identified here promote CaSR conformations that more closely resemble the activated state than those induced by the established drugs.

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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