1. Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin
- Author
-
Jeffrey Comer, Vitelbina Núñez, Jaime Andrés Pereañez, Lina María Preciado, and Paola Rey-Suárez
- Subjects
0301 basic medicine ,Models, Molecular ,Matrix metalloproteinase inhibitor ,Pharmaceutical Science ,Venom ,Matrix metalloproteinase ,Pharmacology ,Analytical Chemistry ,chemistry.chemical_compound ,Mice ,Catalytic Domain ,Drug Discovery ,Edema ,Bothrops ,Enzyme Inhibitors ,Flavonoides ,Creatine Kinase ,Inhibidores de la Metaloproteinasa de la Matriz ,Metalloproteinase ,snake venom metalloproteinase ,biology ,Chemistry (miscellaneous) ,Snake venom ,Molecular Medicine ,Myricetin ,Snake Venoms ,Hemorrhage ,Matrix Metalloproteinase Inhibitors ,Molecular Dynamics Simulation ,Article ,lcsh:QD241-441 ,03 medical and health sciences ,Inhibitory Concentration 50 ,lcsh:Organic chemistry ,Crotalid Venoms ,Animals ,Physical and Theoretical Chemistry ,Envenomation ,free-energy calculations ,Flavonoids ,030102 biochemistry & molecular biology ,Dose-Response Relationship, Drug ,Organic Chemistry ,local tissue damage ,Hydrogen Bonding ,biology.organism_classification ,Simulación de Dinámica Molecular ,030104 developmental biology ,chemistry ,Metalloproteases ,Venenos de Serpiente - Abstract
Most of the snakebite envenomations in Central and South America are caused by species belonging to Bothrops genus. Their venom is composed mainly by zinc-dependent metalloproteinases, responsible of the hemorrhage characteristic of these envenomations. The aim of this study was to determine the inhibitory ability of ten flavonoids on the in-vitro proteolytic activity of Bothrops atrox venom and on the hemorrhagic, edema-forming and myonecrotic activities of Batx-I, the most abundant metalloproteinase isolated from this venom. Myricetin was the most active compound, exhibiting an IC 50 value of 150 μ M and 1021 μ M for the inhibition of proteolytic and hemorrhagic activity, respectively. Independent injection experiments, with a concentration of 1600 μ M of myricetin administered locally, immediately after toxin injection, demonstrated a reduction of 28 ± 6 % in the hemorrhagic lesion. Additionally, myricetin at concentrations 800, 1200 and 1600 μ M promoted a reduction in plasma creatine kinase activity induced by Batx-I of 21 ± 2 % , 60 ± 5 % and 63 ± 2 % , respectively. Molecular dynamics simulations coupled with the adaptive biasing method suggest that myricetin can bind to the metalloproteinase active site via formation of hydrogen bonds between the hydroxyl groups 3’, 4’ and 5’ of the benzyl moiety and amino acid Glu143 of the metalloproteinase. The hydroxyl substitution pattern of myricetin appears to be essential for its inhibitory activity. Based on this evidence, myricetin constitutes a candidate for the development of inhibitors to reduce local tissue damage in snakebite envenomations.
- Published
- 2018