Discovery of potent indoleamine 2,3-dioxygenase (IDO) inhibitor from alkaloids in Picrasma quassioides by virtual screening and in vitro evaluation

Indoleamine 2,3-dioxygenase (IDO) is one of the important targets for cancer immunotherapy through tryptophan pathway. Recently it has being paid great attention to search potent and safe IDO inhibitor from small-molecule compounds. Picrasma quassioides is a kind of medicinal plant abundant with tryptophan-derived indole alkaloids . By virtual screening and kinetic method for enzymatic analysis, lead compounds with potential IDO inhibitory activity were discovered for the first time from PQAs, the natural alkaloids in Picrasma quassioides . The results based on molecular docking analysis and structure-activity relationship (SAR) study demonstrated that coordinating with ferrous ion on the active site of IDO has a great impact on the inhibition potency, and β -carboline with carboxyl substituted on C-1 is the key pharmacophore for IDO inhibition of PQAs. Enzymatic assay provided further evidence for the effectiveness of β -carboline-1-carboxylic acid, which displayed as the most potent competitive inhibitor of IDO among these PQAs, and is even more potent than the recognized positive control 1-methyl tryptophan. This natural tryptophan-derived alkaloid thus deserved further deep research as a promising IDO modulator for cancer immunotherapy.