Inhibition of Resveratrol Analogs on Human and Rat 3ß-Hydroxysteroid Dehydrogenases: Structure-Activity Relationship and Docking Analysis.

Resveratrol and its analogs are phytochemicals. Human 3ß-hydroxysteroid dehydrogenase 1 (3ß-HSD1) synthesizes steroid hormones for normal pregnancy or promoting cancer metastasis. Whether they inhibit 3ß-HSD1 remains unclear. In this study, the inhibitory potency, mode of action, structure-activity relationship, and docking parameters of resveratrol and its analogs on 3ß-HSD1 and rat homolog 3ß-HSD4 were analyzed. The inhibitory potency of these chemicals on human 3ß-HSD1 was 4,4'-dihydroxystilbene (IC50, 3.68 µM) > pinostilbene (8.07 µM) > pinosylvin (10.60 µM) > lunularin (26.84 µM) > resveratrol (30.20 µM) > dihydroresveratrol (>100 µM) = oxyresveratrol (>100 µM) > dihydropinosylvin (ineffective at 100 µM). Resveratrol analogs and metabolites are mixed or competitive inhibitors of human 3ß-HSD1. Resveratrol and 4,4'-dihydroxystilbene inhibited progesterone secretion by human JAr cells at ≥1 µM. Resveratrol (IC50, 32.09 µM) and pinosylvin (34.71 µM) significantly inhibited rat placental 3ß-HSD4 activity. Docking analysis shows that resveratrol analogs and metabolites bind the steroid-binding sites of human 3ß-HSD1 and rat 3ß-HSD4 and interact with the catalytic residues Ser125/Thr125 and Tyr155. The negative correlation of LogP and IC50 values for human 3ß-HSD1 indicates that lipophilicity of chemicals plays a critical role in the inhibitory effect of chemicals. In conclusion, 4,4'-dihydroxystilbene, pinostilbene, and pinosylvin effectively inhibit human 3ß-HSD1 depending on their lipophilicity, thereby acting as potential therapeutic agents.