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

Autor: Liu F; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA., Wu CG; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA., Tu CL; San Francisco VA Medical Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA., Glenn I; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA., Meyerowitz J; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA., Kaplan AL; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA., Lyu J; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA., Cheng Z; San Francisco VA Medical Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA., Tarkhanova OO; Chemspace LLC, 02094 Kyiv, Ukraine., Moroz YS; Chemspace LLC, 02094 Kyiv, Ukraine.; Department of Chemistry, Taras Shevchenko National University of Kyiv, 01601 Kyiv, Ukraine.; Enamine Ltd., 02094 Kyiv, Ukraine., Irwin JJ; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA., Chang W; San Francisco VA Medical Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA., Shoichet BK; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA., Skiniotis G; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2024 Sep 20; Vol. 385 (6715), pp. eado1868. Date of Electronic Publication: 2024 Sep 20.
DOI: 10.1126/science.ado1868
Abstrakt: 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.
Databáze: MEDLINE
Nepřihlášeným uživatelům se plný text nezobrazuje