title: Glycolic acid inhibits enzymatic, hemorrhagic and edema-inducing activities of BaP1, a P-I metalloproteinase from Bothrops asper snake venom: insights from docking and molecular modeling.
abstract: 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 BaP1, a P-I metalloproteinase from Bothrops asper venom, which induces a variety of toxic actions. Glycolic acid inhibited the proteolytic activity of BaP1 on azocasein, with an IC₅₀ of 1.67 mM. The compound was also effective at inhibiting the hemorrhagic activity of BaP1 in skin and muscle in experiments involving preincubation of enzyme and inhibitor prior to injection. When BaP1 was injected i.m. and then, at the same site, 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-dependent manner, edema-forming activity of BaP1 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 with BaP1 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 Glu143, Arg110 and Ala111 of the enzyme. Additionally, molecular modeling results suggest that the inhibitor chelates Zn²⁺, with a distance of 3.58 Å, and may occupy part of substrate binding cleft of BaP1. Our results suggest that glycolic acid is a candidate for the development of inhibitors to be used in snakebite envenomation.
authors.affiliation: Programa de Ofidismo/Escorpionismo, Universidad de Antioquia, A.A. 1226 Medellín, Colombia. andrespj20@yahoo.es
authors.forename: Jaime Andrés
authors.initials: JA
authors.lastname: Pereañez
authors.forename: Arley Camilo
authors.initials: AC
authors.lastname: Patiño
authors.forename: Paola
authors.initials: P
authors.lastname: Rey-Suarez
authors.forename: Vitelbina
authors.initials: V
authors.lastname: Núñez
authors.forename: Isabel Cristina
authors.initials: IC
authors.lastname: Henao Castañeda
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rucavado
mesh_terms: D000818:Animals; D017837:Bothrops; D002364:Caseins / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects; D002614:Chelating Agents / Q000737:chemistry; D004487:Edema / Q000188:drug therapy*; D006016:Glycolates / Q000494:pharmacology*; D006470:Hemorrhage / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D062105:Molecular Docking Simulation; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012909:Snake Bites / Q000188:drug therapy; D012910:Snake Venoms / Q000633:toxicity*; D015032:Zinc / Q000378:metabolism
chemical_list: D002364:Caseins; D002614:Chelating Agents; D006016:Glycolates; D012910:Snake Venoms; C026018:azocasein; C031149:glycolic acid; C104933:BaP1 metalloproteinase; D008666:Metalloendopeptidases; D015032:Zinc
keywords: BaP1; Bothrops asper; Glycolic acid; Local tissue damage; Metalloproteinase