Abstract
Human phospholipase A2 (hPLA2) of the IIA group (HGIIA) catalyzes the hydrolysis of membrane phospholipids, producing arachidonic acid and originating potent inflammatory mediators. Therefore, molecules that can inhibit this enzyme are a source of potential anti-inflammatory drugs, with different action mechanisms of known anti-inflammatory agents. For the study and development of new anti-inflammatory drugs with this action mechanism, snake venom PLA2 (svPLA2) can be employed, since the svPLA2 has high similarity with the human PLA2 HGIIA. Despite the high similarity between these secretory PLA2s, it is still not clear if these toxins can really be employed as an experimental model to predict the interactions that occur with the human PLA2 HGIIA and its inhibitors. Thus, the present study aims to compare and evaluate, by means of theoretical calculations, docking and molecular dynamics simulations, as well as experimental studies, the interactions of human PLA2 HGIIA and two svPLA2s, Bothrops toxin II and Crotoxin B (BthTX-II and CB, respectively). Our theoretical findings corroborate experimental data and point out that the human PLA2 HGIIA and svPLA2 BthTX-II lead to similar interactions with the studied compounds. From our results, the svPLA2 BthTX-II can be used as an experimental model for the development of anti-inflammatory drugs for therapy in humans.
Highlights
The inflammatory process involves a complex cascade of biochemical and cellular events, and it is an innate reaction of the organism that occurs in tissue in response to any cell injury from any dangerous agent: physical, chemical or biological
It is possible to observe that snake venom phospholipases A2 (PLA2) (svPLA2) BthTX-II presented a higher activity and value of inhibition percentage by the vanillic acid (VA)
In relation to the halo of activity (Figure S1 of the Support Material), the sample with the highest proportion of VA presents the lowest activity halo for both enzymes, which indicates that VA decreases the activity of both svPLA2
Summary
The inflammatory process involves a complex cascade of biochemical and cellular events, and it is an innate reaction of the organism that occurs in tissue in response to any cell injury from any dangerous agent: physical, chemical or biological. One of the stages of the inflammatory process is the breakdown of membrane phospholipids by phospholipases A2 (PLA2 ), which generates fatty acids, such as arachidonic acid (AA) and lysophospholipids. Oxidation of AA generates inflammatory mediators, such as prostaglandins, thromboxanes and leukotrienes, through the action of cyclooxygenase (COX) and lipoxygenase (LOX) enzymes. In addition to AA, the breakdown of membrane phospholipids generates lysophospholipids, a precursor of platelet-activating factor (PAF), another potent inflammatory mediator [1,2]. For the treatment of these inflammatory conditions, the Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are the most commonly employed drugs [3]. Their wide use throughout the world is Toxins 2017, 9, 341; doi:10.3390/toxins9110341 www.mdpi.com/journal/toxins
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