{"doi":"10.1126/science.ado1868","title":"Large library docking identifies positive allosteric modulators of the calcium-sensing receptor","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","year":2024,"id":418911,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":45,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9607,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":780135,"name":"Cheng-Guo Wu","orcid":"0000-0003-0514-6474","position":1,"is_corresponding":false},{"id":644080,"name":"Chia‐Ling Tu","orcid":"0000-0002-7323-7733","position":2,"is_corresponding":false},{"id":985400,"name":"Isabella Glenn","orcid":"0009-0002-6443-1873","position":3,"is_corresponding":false},{"id":642233,"name":"Justin Meyerowitz","orcid":"0000-0001-7194-8286","position":4,"is_corresponding":false},{"id":554268,"name":"Anat Levit","orcid":"0000-0002-8217-3225","position":5,"is_corresponding":false},{"id":103658,"name":"Jiankun Lyu","orcid":"0000-0002-0461-5454","position":6,"is_corresponding":false},{"id":268749,"name":"Zhiqiang Cheng","orcid":"0000-0002-4371-0104","position":7,"is_corresponding":false},{"id":36784,"name":"Olga O. Tarkhanova","orcid":"0000-0003-1880-2872","position":8,"is_corresponding":false},{"id":36761,"name":"Yurii S. Moroz","orcid":"0000-0001-6073-002X","position":9,"is_corresponding":false},{"id":36743,"name":"John J. Irwin","orcid":"0000-0002-1195-6417","position":10,"is_corresponding":false},{"id":268743,"name":"Wenhan Chang","orcid":"0000-0001-6583-7176","position":11,"is_corresponding":false},{"id":106698,"name":"Brian K. Shoichet","orcid":"0000-0002-6098-7367","position":12,"is_corresponding":false},{"id":226976,"name":"Georgios Skiniotis","orcid":"0000-0003-0238-7846","position":13,"is_corresponding":false},{"id":1161541,"name":"Fangyu Liu","orcid":"0000-0001-5022-0106","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T01:57:09.067930Z","pmid":"39298584","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}