Effects of gallates on 5α-reductase type 1: structure-activity relationship and implications for neurosteroid balance...

Neurosteroids modulate neural function, with their synthesis dependent on 5α-reductase type 1 (SRD5A1). Dysregulation of SRD5A1 has been implicated in neuropsychiatric disorders. Gallates, naturally occurring polyphenolic compounds, may modulate neurosteroidogenesis. This study aimed to evaluate the effects of gallic acid and eight gallate esters on human and rat SRD5A1 activity and characterize their structure-activity relationship. Using human SF126 glioblastoma cell microsomes and rat brain microsomes, we found inhibitory potency increased with carbon chain length from propyl (C3) to dodecyl (C12) gallate (IC₅₀ values: 168.29 to 20.53 μM), but diminished with cetyl (C16) gallate. Enzyme kinetic analyses revealed mixed/noncompetitive inhibition. Rat SRD5A1 showed reduced sensitivity to shorter-chain gallates compared to human SRD5A1. In intact cells, all active gallates significantly reduced dihydrotestosterone production. Molecular docking simulations showed gallates bind to the NADPH binding site, with binding energies correlating with inhibitory potency (-5.99 to -6.61 kcal/mol). The C16 chain of cetyl gallate extended beyond the optimal binding region, explaining its ineffectiveness at 100 μM. 3D-QSAR modeling identified hydrophobic features as critical for inhibition, while correlation analyses confirmed relationships between inhibitory potency and carbon length (C3-C12) and hydrophobicity properties. These findings provide structural insights for developing selective SRD5A1 modulators with potential applications in neuropsychiatric disorders.