Glycolic acid inhibits enzymatic, hemorrhagic and edema-inducing activities of BaPl, a P-I metalloproteinase from Bottrops asper snake venom: Insights from docking and molecular modeling

摘要

Glycolic acid (GA) (2-Hydroxyethanoic acid) is widely used as chemical peeling agent in Dermatology and, more recently, as a therapeutic and cosmetic compound in the field of skin care and disease treatment. In this work we tested the inhibitory ability of glycolic acid on the enzymatic, hemorrhagic and edema-inducing activities of BaPl, a P-I metalloproteinase from Bothrops asper venom, which induces a variety of toxic actions. Glycolic acid inhibited the proteolytic activity of BaPl on azocasein, with an IC50 of 1.67 mM. The compound was also effective at inhibiting the hemorrhagic activity of BaPl in skin and muscle in experiments involving preincubation of enzyme and inhibitor prior to injection. When BaPl was injected i.m. and then, at the samesite, different concentrations of glycolic acid were administered at either 0 or 5 min, 7 mM solutions of the inhibitor partially abrogated hemorrhagic activity when administered at 0 min. Moreover, glycolic acid inhibited, in a concentration-dependentmanner, edema-forming activity of BaPl in the footpad. In order to have insights on the mode of action of glycolic acid, UV-vis and intrinsic fluorescence studies were performed. Results of these assays suggest that glycolic acid interacts directly withBaPl and chelates the Zn2 ' ion at the active site. These findings were supported by molecular docking results, which suggested that glycolic acid forms hydrogen bonds with residues Glul43, ArgllO and Alalll of the enzyme. Additionally, molecular modeling results suggest that the inhibitor chelates Zn2+, with a distance of 3.58, and may occupy part of substrate binding cleft of BaPl. Our results suggest that glycolic acid is a candidate for the development of inhibitors to be used in snakebite envenomation.