Target prediction and validation of Forsythia suspensa (Thunb.) Vahl for improving Alzheimer's disease

One of the typical pathological features in Alzheimer's disease (AD) is Tau protein hyperphosphorylation. Here, by network pharmacology, 11 potential compounds of Forsythia suspensa (Thunb.) Vahl (FSTV) intervening AD was screened and AKT1, a critical enzyme involved in the Tau phosphorylation, was identified as a target of AD. Among, luteolin, phillyrin, and bicuculline, like the AKT1 agonist SC79, promoted AKT1 activity by binding to PH domain of AKT1, which was demonstrated by molecular docking. Even more, due to the slightly higher binding energy, three compounds bound to AKT1 better than the agonist, mainly through hydrogen bonding, etc. Spectral analysis showed that three compounds all bound with AKT1 to form complexes, and thus quenched the fluorescence of AKT1, with the more significant effects of luteolin and bicuculline on TYR residues of AKT1. Molecular dynamics simulations further indicated that the binding of these compounds to AKT1 occurred near the SER-473 active center of AKT1 and three complexes had relatively stable conformation. In a word, luteolin, phillyrin, and bicuculline from FSTV promoted AKT1 activity to reduce Tau protein hyperphosphorylation, and ultimately improved AD, with luteolin of the best performance.