Citriniti_2025_Arch.Pharm.(Weinheim)_358_e3128

Obesity remains a significant global health concern, with limited pharmacological options that balance efficacy and safety. In this study, we identified lithospermic acid (LTS0059529) from Salvia miltiorrhiza as a potential dual inhibitor of pancreatic lipase (PL) and human carbonic anhydrase VA (hCA VA), two key enzymes in lipid metabolism. Using molecular docking and dynamics simulations, we observed that lithospermic acid interacts with Zn^2 in hCA VA via its benzofuran carboxylate moiety and forms stable complexes with PL through hydrogen bonding with ASP 205 and Pi-stacking interactions with PHE 77 and PHE 215. Experimental validation confirmed its inhibitory activity, with K(i) values of 33.1 +/- 1.6 microM for PL and 0.69 +/- 0.01 microM for hCA VA. While its inhibition of hCA VA is not isoform-specific, lithospermic acid demonstrates significant potential as a dual inhibitor, targeting complementary pathways in obesity management. This study is the first to explore its dual action on PL and hCA VA, highlighting a promising strategy for future antiobesity therapies. Further research will focus on optimizing selectivity and potency to develop safer and more effective treatments.