HXZQCG: A database of natural diverse components in polyherbal formulation HXZQ identified naringenin chalcone as a ligand of H2R

Abstract

Huoxiang Zhengqi (HXZQ) is a classical polyherbal formulation used to treat gastrointestinal disorders. It exerts multi-targeted therapeutic effects, yet its phytochemical complexity hinders standardization and modern pharmacological development. This challenge is further exacerbated by the lack of comprehensive resources covering its diverse natural components, particularly as most previous research neglected peptides and small RNAs, which possess emerging therapeutic potential. There is an urgent need for novel research models to explore polyherbal formulations such as HXZQ. Here, we present the Huoxiang Zhengqi Component Galaxy (HXZQCG), a dedicated database for the HXZQ. HXZQCG integrates over seven million natural components through artificial intelligence-assisted mining, including 15 811 metabolites, 7 597 212 small peptides, and 152 342 small RNAs. To demonstrate its utility, we applied HXZQCG to screen for ligands of the histamine H₂ receptor (H₂R), a well-established and druggable G Protein-Coupled Receptor (GPCR) target widely implicated in gastrointestinal pathologies. Through high-throughput screening of potential ligands for H₂R based on the HXZQCG, we identified 125 candidates. Candidates identified through virtual screening were validated via cell membrane chromatography, ultimately identifying two putative binding small molecules. Furthermore, our results demonstrated that naringenin chalcone is a ligand of H₂R, and it can inhibit the downstream accumulation of cyclic adenosine monophosphate (cAMP). In sum, HXZQCG stands as a representative case study for polyherbal formulation research. It provides data-based resources for discovery of active component and elucidation of pharmacological mechanisms, serving as a fundamental data-driven platform to support the secondary development of HXZQ. HXZQCG is available at https://cbcb.cdutcm.edu.cn/HXZQCG/.