Neuroactive phytochemicals from hawthorn: Preliminary evidence for malic acid and chlorogenic acid as 5-HTR1A ligands with antidepressant potential

Serotonin receptor subtype 1 A (5-HTR 1A ) is a critical therapeutic target for neuropsychiatric disorders. Crataegus pinnatifida Bge. (hawthorn) exhibits potent antidepressant-like effects via 5-HTR 1A activation, yet its bioactive constituents remain unidentified. Herein, we engineered 5-HTR 1A -haloalkane dehalogenase fusion protein and immobilized it on 6-bromohexanoic acid-functionalized microspheres to establish affinity-based screening platform. Bioactivity-guided isolation identified malic acid and chlorogenic acid as 5-HTR 1A ligands, and their binding energies were − 12.9 kcal/mol and − 44.7 kcal/mol, respectively. In vitro assays demonstrated that chlorogenic acid significantly protected PC12 cells from corticosterone-induced damage at concentrations as low as 2.5 μM ( p = 0.0305), whereas malic acid exhibited comparable effects at 20 μM. Both compounds effectively counteracted corticosterone-induced reductions in serotonin, dopamine, and BDNF levels likely through interactions with 5-HTR 1A . Collectively, these findings suggest that malic acid and chlorogenic acid are stable, high-affinity 5-HTR 1A ligands with significant neuroprotective potential, making them promising lead compounds for developing novel 5-HTR 1 A -targeted therapeutics. • 5-HTR 1A is a key therapeutic target for the treatment of neuropsychiatric disorders. • Hawthorn-derived malic acid and chlorogenic acid are novel 5-HTR 1A -targeting ligands. • Both compounds demonstrate high 5-HTR 1A affinity and potent neuroprotective effects. • They are promising candidates for the development of 5-HTR 1A -targeting therapeutics.