The anticancer property of (−)-Kusunokinin is related to CFS1R and AKT pathways, although the protein target has not yet been identified. This research thus aimed to apply molecular docking and molecular dynamics simulation to predict the protein target in the pathways. It was found that aldo-keto reductase family 1 member B1 (AKR1B1) was identified as a (−)-kusunokinin receptor. The binding affinity of (−)-kusunokinin was stronger than the selected aldose reductase inhibitors (ARIs) and the related substrates. Moreover, the compound had no significant effect on AKR1B1 conformation. The findings suggested the similarity of (−)-kusunokinin to ARI. An aromatic ring and a γ-butyrolactone ring shared a role with structural counterparts in known inhibitors. The aromatic group contributed to π−π attraction with Trp111, while the γbutyrolactone ring bound to the catalytic His110 via hydrogen bondings, leading to enzymatic inhibition as a consequence of substrate competitiveness. The potential of (−)-kusunokinin could be further investigated by in vitro and/or in vivo experiments to confirm (−)-kusunokinin as a new AKR1B1 antagonist.

Tanawattanasuntorn, T.; Thongpanchang, T.; Rungrotmongkol, T.; Hanpaibool, C.; Graidist, P.;
Tipmanee, V. ACS Omega 2021, 6, 606−614.