Mas-related G protein-coupled receptor X2 (MRGPRX2) is a novel G protein-coupled receptor (GPCR) that has been identified as a potential therapeutic target for pseudo allergic diseases. The development of novel MRGPRX2 antagonists possesses tremendous therapeutic and social implications. Recent efforts have been invested in finding specific MRGPRX2 inhibitors for potential therapeutic approaches, although none has been approved for clinical use to date. We previously identified Imperatorin (the furanocoumarin compound) as a lead molecule for MRGPRX2 antagonist. In this study, we investigated the anti-pseudo-allergic effect of the fourteen synthesized furanocoumarin derivatives, as well as the relationship between their activity and MRGPRX2 receptor. In vitro and in vivo experimental results showed that compounds XAT-13 and XAT-14 can suppress compound 48/80-induced Mast cells degranulation in a good dose-dependent manner. Molecular docking implied that XAT-13 and XAT 14 may shared the same binding sites with C48/80. Our study revealed that the novel small molecules (XAT-13 and XAT-14) as early-stage lead compounds, which can be further optimized to obtain therapeutic drug candidates to address MRGPRX2 mediated allergic reactions and other inflammatory diseases.

2026-01-01·BIOCHEMICAL PHARMACOLOGY

Efficient screening and evaluation of MRGPRX2 antagonists based on AlphaFold 3

Article

作者: Ma, Mengyang ; Gao, Jie ; Zhang, Yongjing ; Li, Chenjia ; Wang, Nan ; Deng, Tingting ; Zhang, Xinping ; Gao, Chang

Activation of MRGPRX2 directly induces mast cell activation, which is closely related to various allergic inflammatory diseases and could serve as a therapeutic target. However, MRGPRX2 small molecule antagonist drugs have not yet been launched. Virtual screening based on protein structure is an efficient approach for the discovery of small molecule drugs. Nevertheless, the current virtual prediction based on known MRGPRX2 PDB structures is not satisfactory due to the lack of crystallization under inhibitory configuration. In this study, AlphaFold 3 was applied to predict the structure of MRGPRX2 and then used for a Bioactive Compound Library virtual screening using Schrodinger software. The top 30 compounds with the highest scores among 23,562 compounds were selected and validated for their inhibitory effect against Ca²⁺ influx in MRGPRX2-overexpressing HEK293 cells and mast cell degranulation. Further in vivo study indicated that HCH6-1 had a competent cure effect on MRGPRX2-related atopic dermatitis. In addition, cell membrane chromatography (CMC) was also applied to verify the binding characteristic between MRGPRX2 and HCH6-1. Overall, our research demonstrated the use of AlphaFold 3 for protein structure prediction and virtual screening and discovered a novel small molecule MRGPRX2 antagonist.

2025-05-08·ACS Medicinal Chemistry Letters

Novel Bicyclic Heterocycles as MRGPRX2 Antagonists for Treating Inflammatory Diseases

作者: Sabnis, Ram W.

Provided herein are novel bicyclic heterocycles as MRGPRX2 antagonists, pharmaceutical compositions, use of such compounds in treating inflammatory diseases, and processes for preparing such compounds.

100 项与 MRGPRX2 antagonists(Smith, Gambrell & Russell) 相关的药物交易

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