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.