Discovery and characterization of naturally occurring chalcones as potent inhibitors of bile salt hydrolases

Bile salt hydrolases (BSHs) play crucial roles in the deconjugation of conjugated bile acids and therefore are key targets for modulating acid metabolism. This study aimed to identify efficacious BSH inhibitors from a natural compound library characterize their inhibitory mechanisms. The potential more than 100 compounds against produced by Lactobacillus salivarius (lsBSH) was assayed, several chalcones with strong or moderate lsBSH activity were identified. Of all tested chalcones, licochalcone C isobavachalcone showed most potent (IC 50 < 1 μM). Inhibition kinetic analyses demonstrated that both reversibly inhibited lsBSH-catalyzed CA-AMCA hydrolysis via mixed manner. Docking simulations suggested they bind at two distinct sites mainly hydrogen bonding hydrophobic interactions. Additionally, found inhibit various BSHs decrease total mouse feces, thus suggesting these agents broad-spectrum inhibitors. Collectively, our findings revealed naturally occurring BSH, which may serve as promising lead development