Discovery and characterization of novel hematopoietic prostaglandin D synthase inhibitors from traditional Chinese medicine: the bioactive potential of dihydroberberine in treatments of Duchenne muscular dystrophy and inflammation-related diseases.

Inflammation plays a central role in various diseases, necessitating effective anti-inflammatory agents. Prostaglandin D2 (PGD2), a key mediator synthesised by haematopoietic prostaglandin D synthase (H-PGDS), is linked to allergic and inflammatory conditions. This study employed pharmacophore-based screening to identify inhibitors targeting H-PGDS. The model Phar-A2HR2 identified EMy (IC50 = 88.9 ± 1.1 µM) as a potential inhibitor. Further analysis revealed that its analog EMy-5 (dihydroberberine) demonstrated the most potent inhibitory activity (IC₅₀ = 3.7 ± 1.1 µM) and binding affinity (KD = 3.2 ± 0.74 µM). Molecular dynamics simulations revealed stabilising interactions, including π-π stacking, hydrogen bonding, and hydrophobic contacts, in the H-PGDS-EMy-5 complex. Functional assays confirmed that EMy-5 significantly reduced PGD2 production in KU812 cells. These findings highlight EMy-5 as a promising candidate for the treatment of inflammatory and allergic diseases, including Duchenne muscular dystrophy, demonstrating both potent inhibitory activity and strong binding characteristics.