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

• 成果类型: Article
• 署名作者: Liu, Fangyu; Wu, Cheng-Guo; Tu, Chia-Ling; Glenn, Isabella; Meyerowitz, Justin; Kaplan, Anat Levit; Lyu, Jiankun; Cheng, Zhiqiang; Tarkhanova, Olga O.; Moroz, Yurii S.; Irwin, John J.; Chang, Wenhan; Shoichet, Brian K.; Skiniotis, Georgios
• 署名单位: University of California System; University of California San Francisco; Stanford University; University of California System; University of California San Francisco; US Department of Veterans Affairs; Veterans Health Administration (VHA); San Francisco VA Medical Center; Ministry of Education & Science of Ukraine; Taras Shevchenko National University of Kyiv; Enamine Ltd; Stanford University; Rockefeller University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9364
• DOI: 10.1126/science.ado1868
• 发表日期: 2024-09-20
• 关键词: chronic kidney-disease; secondary hyperparathyroidism; ca2+-sensing receptor; parathyroid-hormone; protein; DISCOVERY; activation; cinacalcet; mutations; etelcalcetide

摘要

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.