ArticleScience (New York, N.Y.)2024
Large library docking identifies positive allosteric modulators of the calcium-sensing receptor.
Article in Science (New York, N.Y.), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Docking-based virtual screening: Past, present, and future.Biophysical journal · 2026Review
- Pushing the boundaries of virtual screening scale of combinatorial spaces with the V-SYNTHES approach.npj drug discovery · 2026Article
- Chemical Distance-Based Acceleration of Large Library Docking with ChemSTEP.ACS central science · 2026Article
- Modeling the Sensitivity of Large-Scale Virtual Screening to Scoring Function Accuracy, Artifacts, and Library Composition.Journal of chemical information and modeling · 2026Article
- Library Docking for Cannabinoid-2 Receptor Ligands.Journal of medicinal chemistry · 2026Article
- Targeting frizzled receptors (FZDs) for anti-tumor therapy: From orthosteric to allosteric inhibition.Acta pharmaceutica Sinica. B · 2026Review
- The Selectivity Implications of Docking Libraries with Greater and Lesser Similarities to Bio-like Molecules.Journal of medicinal chemistry · 2026Article
- Evocalcet improved the PTH-calcium setpoint and suppressed parathyroid proliferation in mice model of primary hyperparathyroidism.Journal of bone and mineral metabolism · 2026Article
- Fibrosis suppressive effect and mechanism of CaSR positive allosteric modulators/p-dioxanone copolymers.Drug delivery and translational research · 2026Article
- Open-Source Molecular Docking and AI-Augmented Structure-Based Drug Design: Current Workflows, Challenges, and Opportunities.International journal of molecular sciences · 2026Review
- Article
- Library docking for Cannabinoid-2 Receptor ligands.bioRxiv : the preprint server for biology · 2026Article
- Calcium-Sensing Receptor Regulation of Gastrointestinal Hormone Secretion.Endocrine reviews · 2026Review
- The selectivity implications of docking libraries with greater and lesser similarities to bio-like molecules.bioRxiv : the preprint server for biology · 2026Article
- Modulated calcium-sensing receptor (CaSR) expression in human breast cancer provided insights into tumor progression and therapeutic potential.Journal of the Egyptian National Cancer Institute · 2026Article
- Calcimimetics and CaSR signaling in CKD-MBD: bone-immune-vascular crosstalk and therapeutic potential.Frontiers in immunology · 2026Review
- Large scale prospective evaluation of co-folding across 557 Mac1-ligand complexes and three virtual screens.bioRxiv : the preprint server for biology · 2025Article
- Calcium-sensing receptor: a potential target for liver health and diseases.Journal of translational medicine · 2025Review
- A novel chemoreactive calcilytic for the potential treatment of autosomal dominant hypocalcemia.Acta pharmaceutica Sinica. B · 2025Article
- Docking 14 Million Virtual Isoquinuclidines against the μ and κ Opioid Receptors Reveals Dual Antagonists-Inverse Agonists with Reduced Withdrawal Effects.ACS central science · 2025Article
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14 authors.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.