EMD-45127
Structure of Calcium-Sensing Receptor in complex with positive allosteric modulator '6218
EMD-45127
Composite mapSingle-particle
2.8 Å
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Map released: 02/10/2024
Last modified: 16/10/2024
Sample Organism:
Homo sapiens
Sample: Calcium-sensing receptor bound to compound '6218
Fitted models: 9c1p (Avg. Q-score: 0.568)
Deposition Authors: Wu C, Skiniotis G
Sample: Calcium-sensing receptor bound to compound '6218
Fitted models: 9c1p (Avg. Q-score: 0.568)
Deposition Authors: Wu C, Skiniotis G
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Large library docking identifies positive allosteric modulators of the calcium-sensing receptor.
Liu F
,
Wu CG
,
Tu CL,
Glenn I
,
Meyerowitz J
,
Kaplan AL
,
Lyu J
,
Cheng Z,
Tarkhanova OO
,
Moroz YS
,
Irwin JJ
,
Chang W
,
Shoichet BK
,
Skiniotis G
(2024) Science , 385 , eado1868 - eado1868
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(2024) Science , 385 , eado1868 - eado1868
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.
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.