{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Liu F"],"funding":["BLRD VA","NIDDK NIH HHS","NIA NIH HHS","NINDS NIH HHS","NIAMS NIH HHS","NIGMS NIH HHS"],"pagination":["eado1868"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11629082"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["385(6715)"],"pubmed_abstract":["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."],"journal":["Science (New York, N.Y.)"],"pubmed_title":["Large library docking identifies positive allosteric modulators of the calcium-sensing receptor."],"pmcid":["PMC11629082"],"funding_grant_id":["R01 GM071896","IK6 BX004835","R01 DK132902","R01 DK122259","R01 NS122394","I01 BX005851","R21 AG070721","RF1 AG075742","P30 AR075055","P30 AR066262","R35 GM122481"],"pubmed_authors":["Glenn I","Kaplan AL","Irwin JJ","Meyerowitz J","Tarkhanova OO","Shoichet BK","Cheng Z","Chang W","Lyu J","Moroz YS","Skiniotis G","Wu CG","Tu CL","Liu F"],"additional_accession":[]},"is_claimable":false,"name":"Large library docking identifies positive allosteric modulators of the calcium-sensing receptor.","description":"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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Sep","modification":"2026-06-03T11:26:09.392Z","creation":"2026-04-27T03:10:29.759Z"},"accession":"S-EPMC11629082","cross_references":{"pubmed":["39298584"],"doi":["10.1126/science.ado1868"]}}