Discovery of CaSR Peptide Agonists via Multistage Screening: <i>In Silico</i> Design, <i>In Vitro</i> Validation, and <i>In Vivo</i> Efficacy
Human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) that directly regulates parathyroid hormone release and maintains calcium homeostasis. The discovery of potent CaSR agonists with computer-aided drug design (CADD) has been appealing. Herein, we report the discovery of a series of new CaSR agonists by enhancing the molecular binding affinity through the replacement of key residues via the iCVETide platform. Ac-<sub>D</sub>-Cys(<sub>L</sub>-Cys)-<sub>D</sub>-Arg-<sub>D</sub>-(3-Gu)-Phe-<sub>D</sub>-Abu-<sub>D</sub>-Arg-<sub>D</sub>-Ala-<sub>D</sub>-Arg-NH<sub>2</sub> (compound <b>6g</b>) with an outstanding activity and a satisfactory ADME profile is discovered, and the interaction mode between <b>6g</b> and CaSR is elucidated through molecular docking and molecular dynamics simulations, showing hydrogen bonds, salt bridges, and π-π stacking. In addition, <b>6g</b> is capable of activating human CaSR as a calcimimetic positive allosteric modulator. Our results provide a viable alternative to approved calcimimetics and a novel protocol for the discovery of CaSR agonists.
Authors
- Xiaobin Qin
- Xuan Tang (ORCID: https://orcid.org/0000-0002-8883-0994)
- Xiaomin Liu (ORCID: https://orcid.org/0000-0002-9258-4087)
- Binbin Xu (ORCID: https://orcid.org/0000-0002-0822-5250)
- Ling Zhou (ORCID: https://orcid.org/0000-0002-6805-2961)
- Guangpeng Meng
- Bo Huang (ORCID: https://orcid.org/0000-0002-3028-1945)
- Yuqing Guan
- Lan Zhang (ORCID: https://orcid.org/0009-0009-3743-0024)
- Li Yuanbo (ORCID: https://orcid.org/0009-0008-6552-7205)
- Haixia Liu (ORCID: https://orcid.org/0000-0001-7267-2824)
- Yu Yuan (ORCID: https://orcid.org/0000-0001-5441-8742)
- Zhen Shi
- Yingmiao Pan (ORCID: https://orcid.org/0009-0008-6270-9038)
- G. Xue (ORCID: https://orcid.org/0009-0008-0012-4915)
Institutions
- Shenyang Pharmaceutical University (CN)
- Chengdu Medical College (CN)
- China National Pharmaceutical Group Corporation (China) (CN)
- Czech Academy of Sciences, Institute of Biotechnology (CZ)
- Innovative Clinical Research (US)
- Chengdu Center for Disease Control and Prevention (CN)
- Drug Discovery Laboratory (Norway) (NO)
- ZheJiang Institute For Food and Drug Control (CN)
- Ministry of Education (BD)
- Innovative Research (United States) (US)
- State Institute for Drug Control (CZ)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-09-25
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01119
- Citations
- 1
- Primary Topic
- Molecular Sensors and Ion Detection
- Type
- article
- Field-Weighted Citation Impact
- 0.76