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.
Authors
- Jiankun Lyu (ORCID: https://orcid.org/0000-0002-0461-5454)
- Yurii S. Moroz (ORCID: https://orcid.org/0000-0001-6073-002X)
- Brian K. Shoichet (ORCID: https://orcid.org/0000-0002-6098-7367)
- Wenhan Chang (ORCID: https://orcid.org/0000-0001-6583-7176)
- Anat Levit (ORCID: https://orcid.org/0000-0002-8217-3225)
- Justin Meyerowitz (ORCID: https://orcid.org/0000-0001-7194-8286)
- Georgios Skiniotis (ORCID: https://orcid.org/0000-0003-0238-7846)
- Chia‐Ling Tu (ORCID: https://orcid.org/0000-0002-7323-7733)
- John J. Irwin (ORCID: https://orcid.org/0000-0002-1195-6417)
- Olga O. Tarkhanova (ORCID: https://orcid.org/0000-0003-1880-2872)
- Isabella Glenn (ORCID: https://orcid.org/0009-0002-6443-1873)
- Cheng-Guo Wu (ORCID: https://orcid.org/0000-0003-0514-6474)
- Fangyu Liu (ORCID: https://orcid.org/0000-0001-5022-0106)
- Zhiqiang Cheng (ORCID: https://orcid.org/0000-0002-4371-0104)
Institutions
- San Francisco VA Medical Center (US)
- University of California, San Francisco (US)
- Taras Shevchenko National University of Kyiv (UA)
- University of California San Francisco Medical Center (US)
- DigitalSpace (United States) (US)
- Enamine (Ukraine) (UA)
- Stanford University (US)
Publication Details
- Journal
- Science
- Published
- 2024-09-19
- DOI
- https://doi.org/10.1126/science.ado1868
- Citations
- 34
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 7.95
Funders
- U.S. Department of Veterans Affairs
- Damon Runyon Cancer Research Foundation
- National Institutes of Health