biostudies-literatureLiu FBLRD VANIDDK NIH HHSNIA NIH HHSNINDS NIH HHSNIAMS NIH HHSNIGMS NIH HHSeado1868https://www.ebi.ac.uk/biostudies/studies/S-EPMC11629082biostudies-literatureUnknown385(6715)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.Science (New York, N.Y.)Large library docking identifies positive allosteric modulators of the calcium-sensing receptor.PMC11629082R01 GM071896IK6 BX004835R01 DK132902R01 DK122259R01 NS122394I01 BX005851R21 AG070721RF1 AG075742P30 AR075055P30 AR066262R35 GM122481Glenn IKaplan ALIrwin JJMeyerowitz JTarkhanova OOShoichet BKCheng ZChang WLyu JMoroz YSSkiniotis GWu CGTu CLLiu FfalseLarge 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.2024-01-01T00:00:00Z2024 Sep2026-06-03T11:26:09.392Z2026-04-27T03:10:29.759ZS-EPMC116290823929858410.1126/science.ado1868