Demethoxylation of curcumin enhances its inhibition on human and rat 178-hydroxysteroid dehydrogenase 3: QSAR structure-activity relationship and in silico docking analysis

Curcuminoids have many pharmacological effects. They or their metabolites may have side effects by suppressing 178-hydroxysteroid dehydrogenase 3 (178-HSD3). Herein, we investigated the inhibition of curcuminoids and their metabolites on human and rat 178-HSD3 and analyzed their structure-activity relationship (SAR) and performed in silico docking. Curcuminoids and their metabolites ranked in terms of IC50 values against human 178-HSD3 were bisdemethoxycurcumin (0.61 mu M) > curcumin (8.63 mu M) > demethoxycurcumin (9.59 mu M) > tetrahydrocurcumin (22.04 mu M) > cyclocurcumin (29.14 mu M), and those against rat 178-HSD3 were bisdemethoxycurcumin (3.94 mu M) > demethoxycurcumin (4.98 mu M) > curcumin (9.62 mu M) > tetrahydrocurcumin (45.82 mu M) > cyclocurcumin (143.5 mu M). The aforementioned chemicals were mixed inhibitors for both enzymes. Molecular docking analysis revealed that they bind to the domain between the androstenedione and NADPH active sites of 178-HSD3. Bivariate correlation analysis showed a positive correlation between LogP and pKa of curcumin derivatives with their IC50 values. Additionally, a 3D-QSAR analysis revealed that a pharmacophore model consisting of three hydrogen bond acceptor regions and one hydrogen bond donor region provided a better fit for bisdemethoxycurcumin compared to curcumin. In conclusion, curcuminoids and their metabolites possess the ability to inhibit androgen biosynthesis by directly targeting human and rat 178-HSD3. The inhibitory strength of these compounds is influenced by their lipophilicity and ionization characteristics.