Characterization of Dicaffeoylspermidine Derivatives from Wolfberry as Potent and Selective Inhibitors of Human Cytochrome P450 46A1 In vitro

Abstract

Background: Cytochrome P450 (CYP) 46A1 enzyme is a neuro-specific metabolic enzyme that converts cholesterol to 24-hydroxycholesterol. Inhibition of CYP46A1 activity is of great significance to improve neurodegenerative disorder. Objective: The present study aimed to investigate the inhibitory effect of wolfberry dicaffeoylspermidine derivatives on CYP46A1. Methods: The inhibitory effect of six wolfberry dicaffeoylspermidine derivatives on CYP46A1 activity was investigated using cholesterol as a substrate in vitro. Molecular docking was used to simulate the interactions between wolfberry dicaffeoylspermidine derivatives and CYP46A1. Results: Of these spermidines, lycibarbarspermidines D (1) and A (2) showed highly-selective and strong inhibitory effects on CYP46A1 but not on other human CYP isoforms. Both 1 and 2 exhibit mixed partial competitive inhibition of CYP46A1, with Ki values of 106 nM and 258 nM, respectively. Notably, 1 and 2 had excellent orientations within the active cavity of CYP46A1, and both formed three water-hydrogen bonds with W732 and W765, located near the heme of CYP46A1. Conclusion: Compounds 1 and 2 showed a highly-selective and nanomolar affinity for CYP46A1 in vitro. These findings suggested that compounds 1 and 2 could be used as potent inhibitors of CYP46A1 in vitro.