As polyphenolic compounds isolated from plants extracts, flavonoids have been applied to various pharmaceutical uses in recent decades due to their anti-inflammatory, cancer preventive, and cardiovascular protective activities. In this study, we evaluated the effects of the flavonoid quercetin on Crotalus durissus terrificus secretory phospholipase A2 (sPLA2), an important protein involved in the release of arachidonic acid from phospholipid membranes. The protein was chemically modified by treatment with quercetin, which resulted in modifications in the secondary structure as evidenced through circular dichroism. In addition, quercetin was able to inhibit the enzymatic activity and some pharmacological activities of sPLA2, including its antibacterial activity, its ability to induce platelet aggregation, and its myotoxicity by approximately 40%, but was not able to reduce the inflammatory and neurotoxic activities of sPLA2. These results suggest the existence of two pharmacological sites in the protein, one that is correlated with the enzymatic site and another that is distinct from it. We also performed molecular docking to better understand the possible interactions between quercetin and sPLA2. Our docking data showed the existence of hydrogen-bonded, polar interactions and hydrophobic interactions, suggesting that other flavonoids with similar structures could bind to sPLA2. Further research is warranted to investigate the potential use of flavonoids as sPLA2 inhibitors. © 2010 Elsevier Ireland Ltd. All rights reserved.18901/02/15916Kini, R., Excitement ahead: Structure, function and mechanism of snake venom phospholipase A2 enzymes (2003) Toxicon, 42 (8), pp. 827-840Nevalainen, T., Graham, G., Scott, K., Antibacterial actions of secreted phospholipases A2. Review (2008) Biochim. Biophys. Acta, 1781 (12), pp. 1-9Burke, J., Dennis, E., Phospholipase A2 biochemistry (2009) Cardiovasc. Drugs Ther., 23 (1), pp. 49-59Evangelista, J., Martins, A., Nascimento, N., Sousa, C., Alves, R., Toyama, D., Toyama, M., Monteiro, H., Renal and vascular effects of the natriuretic peptide isolated from Crotalus durissus cascavella venom (2008) Toxicon, 52 (7), pp. 737-744Soares, A., Giglio, J., Chemical modifications of phospholipases A2 from snake venoms: Effects on catalytic and pharmacological properties (2003) Toxicon, 42 (8), pp. 855-868Kini, R., Chan, Y., Accelerated evolution and molecular surface of venom phospholipase A2 enzymes (1999) J. Mol. Evol., 48 (2), pp. 125-132Chakraborti, S., Phospholipase A(2) isoforms: A perspective (2003) Cell Signal., 15 (7), pp. 637-665Lättig, J., Böhl, M., Fischer, P., Tischer, S., Tietböhl, C., Menschikowski, M., Gutzeit, H., Pisabarro, M., Mechanism of inhibition of human secretory phospholipase A2 by flavonoids: Rationale for lead design (2007) J. Comput. Aided Mol. Des., 21 (8), pp. 473-483Di Carlo, G., Mascolo, N., Izzo, A., Capasso, F., Flavonoids: Old and new aspects of a class of natural therapeutic drugs (1999) Life Sci., 65 (4), pp. 337-353Gil, B., Sanz, M., Terencio, M., Gunasegaran, R., Paya, M., Alcaraz, M., Morelloflavone, a novel biflavonoid inhibitor of human secretory phospholipase A(2) with anti-inflammatory activity (1997) Biochem. Pharmacol., 53, p. 733Lindahl, M., Tagesson, C., Flavonoids as phospholipase A2 inhibitors: Importance of their structure for selective inhibition of group II phospholipase A2 (1997) Inflammation, 21 (3), pp. 347-356Iglesias, C., Aparicio, R., Rodrigues-Simioni, L., Camargo, E., Antunes, E., Marangoni, S., De Oliveira Toyama, D., Toyama, M., Effects of morin on snake venom phospholipase A2 (PLA2) (2005) Toxicon, 46 (7), pp. 751-758Lindahl, M., Tagesson, C., Selective inhibition of group II phospholipase A2 by quercetin (1993) Inflammation, 17 (5), pp. 573-582Toyama, M.H., De Oliveira, D.G., Beriam, L.O.S., Novello, J.C., Rodrigues-Simioni, L., Marangoni, S., Structural, enzymatic and biological properties of new PLA2 isoform from Crotalus durissus terrificus venom (2003) Toxicon, 41 (8), pp. 1033-1038. , DOI 10.1016/S0041-0101(03)00085-0Zhao, H., Tang, L., Wang, X., Zhou, Y., Lin, Z., Structure of a snake venom phospholipase A2 modified by p-bromo-phenacyl-bromide (1998) Toxicon, 36 (6), pp. 875-886Laemmli, U., Cleavage of structural proteins during the assembly of the head of bacteriophage T4 (1970) Nature, 227 (5259), pp. 680-685Wen-Hwa, L., Toyama, M.H., Soares, A.M., Giglio, J.R., Marangoni, S., Polikarpov, I., Crystallization and preliminary X-ray diffraction studies of piratoxin III, a D-49 phospholipase A2 from the venom of Bothrops pirajai (1999) Acta Crystallographica Section D: Biological Crystallography, 55 (6), pp. 1229-1230. , DOI 10.1107/S0907444999004576Santi-Gadelha, T., Rocha, B., Oliveira, C., Aragão, K., Marinho, E., Gadelha, C., Toyama, M., Cavada, B., Purification of a PHA-like chitin-binding protein from Acacia farnesiana seeds: A time-dependent oligomerization protein (2008) Appl. Biochem. Biotechnol., 150 (1), pp. 97-111Toyama, M., Toyama, D.O., Passero, L., Laurenti, M., Corbett, C., Tomokane, T., Fonseca, F., Fonteles, M., Isolation of a new l-amino acid oxidase from Crotalus durissus cascavella venom (2006) Toxicon, 47 (1), pp. 47-57Ginsborg, B., Warriner, J., The isolated chick biventer cervicis nerve-muscle preparation (1960) Br. J. Pharmacol. Chemother., 15, pp. 410-411Dewar, M.J.S., Zoebisch, E.G., Healy, E.F., Stewart, J.J.P., Development and use of quantum mechanical molecular models. 76. AM1: A new general purpose quantum mechanical molecular model (1985) J. Am. Chem. Soc., 107 (13), p. 8Jones, G., Willett, P., Glen, R., Leach, A., Taylor, R., Development and validation of a genetic algorithm for flexible docking (1997) J. Mol. Biol., 267 (3), pp. 727-748Verheij, H., Volwerk, J., Jansen, E., Puyk, W., Dijkstra, B., Drenth, J., De Haas, G., Methylation of histidine-48 in pancreatic phospholipase A2. Role of histidine and calcium ion in the catalytic mechanism (1980) Biochemistry, 19 (4), pp. 743-750Scott, D., Sigler, P., Structure and catalytic mechanism of secretory phospholipases A2 (1994) Adv. Protein Chem., 45, pp. 53-88Gil, B., Sanz, M., Terencio, M., Ferrándiz, M., Bustos, G., Payá, M., Gunasegaran, R., Alcaraz, M., Effects of flavonoids on Naja naja and human recombinant synovial phospholipases A2 and inflammatory responses in mice (1994) Life Sci., 54 (20), pp. 333-338Fonseca, F., Antunes, E., Morganti, R., Monteiro, H., Martins, A., Toyama, D., Marangoni, S., Toyama, M., Characterization of a new platelet aggregating factor from crotoxin Crotalus durissus cascavella venom (2006) Protein J., 25 (3), pp. 183-192Soares, A., Mancin, A., Cecchini, A., Arantes, E., Frana, S., Gutiérrez, J., Giglio, J., Effects of chemical modifications of crotoxin B, the phospholipase A(2) subunit of crotoxin from Crotalus durissus terrificus snake venom, on its enzymatic and pharmacological activities (2001) Int. J. Biochem. Cell Biol., 33 (9), pp. 877-888Diz Filho, E., Marangoni, S., Toyama, D., Fagundes, F., Oliveira, S., Fonseca, F., Calgarotto, A., Toyama, M., Enzymatic and structural characterization of new PLA2 isoform isolated from white venom of Crotalus durissus ruruima (2009) Toxicon, 53 (1), pp. 104-114Buckland, A., Wilton, D., The antibacterial properties of secreted phospholipases A(2) (2000) Biochim. Biophys. Acta, 1488 (12), pp. 71-82Kim, H., Pham, H., Ziboh, V., Flavonoids differentially inhibit guinea pig epidermal cytosolic phospholipase A2 (2001) Prostaglandins Leukot. Essent. Fatty Acids, 65 (56), pp. 281-286Toyama, D., Marangoni, S., Diz-Filho, E., Oliveira, S., Toyama, M., Effect of umbelliferone (7-hydroxycoumarin, 7-HOC) on the enzymatic, edematogenic and necrotic activities of secretory phospholipase A2 (sPLA2) isolated from Crotalus durissus collilineatus venom (2009) Toxicon, 53 (4), pp. 417-426Ohno, M., Chijiwa, T., Oda-Ueda, N., Ogawa, T., Hattori, S., Molecular evolution of myotoxic phospholipases A2 from snake venom (2003) Toxicon, 42 (8), pp. 841-854Valentin, E., Lambeau, G., Increasing molecular diversity of secreted phospholipases A(2) and their receptors and binding proteins (2000) Biochim. Biophys. Acta, 1488 (12), pp. 59-70Halperin, I., Ma, B., Wolfson, H., Nussinov, R., Principles of docking: An overview of search algorithms and a guide to scoring functions (2002) Proteins, 47 (4), pp. 409-443