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Type: Artigo de periódico
Title: Molecular Modeling And Inhibition Of Phospholipase A2 By Polyhydroxy Phenolic Compounds
Author: da Silva S.L.
Calgarotto A.K.
Maso V.
Damico D.C.S.
Baldasso P.
Veber C.L.
Villar J.A.F.P.
Oliveira A.R.M.
Comar Jr. M.
Oliveira K.M.T.
Marangoni S.
Abstract: Phospholipases A2 are enzymes responsible for the hydrolysis of membrane phospholipids that release arachidonic acid, which serves as substrate for pro-inflammatory mediators, such as prostaglandins and leucotriens. The design of specific inhibitors for PLA2 might help in the development of new anti-inflammatory drugs. Polyhydroxy phenolic compounds, such as flavonoids, vitamin E, rosmarinic acid and aristolochic acid, are able to inhibit PLA2 from different sources. Herein, we have studied the kinetic behavior and the capacity of inhibiting edema formation induced by PLA2 of five different polyhydroxy phenolic compounds (two phenolic derivatives and three acetophenone hydroxylated derivatives) extracted from the venom of Crotalus adamanteus. The results showed that compounds 1,3-dihydroxy benzene, 1,3,5-trihydroxy benzene and 2,4,6-trihydroxy acetophenone were the most efficient in the inhibition of the enzymatic activity and edema induction by PLA2. It was also verified that the number of hydroxyls in each molecule is not a limiting factor for the inhibition capacity of these compounds. Molecular modeling studies indicated that the most active compounds are linked to the amino acid Asp 49 and that they destabilize the coordination of the calcium atom, which is essential to the catalytic activity. The study of potential surfaces showed that there are conditions in which the potential values must be adequate for enzyme complex formation with polyhydroxy phenolic compounds. When the potential over the hydroxyl surfaces is very high, formation of stable complexes does not occur and the enzyme does not act intensely. These results might be helpful in the design of a drug that specifically inhibits PLA2. © 2008 Elsevier Masson SAS. All rights reserved.
Rights: fechado
Identifier DOI: 10.1016/j.ejmech.2008.02.043
Date Issue: 2009
Appears in Collections:Unicamp - Artigos e Outros Documentos

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