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 M, Oliveira K M T, Marangoni S
Depto de Química, ICE, Universidade Federal do Amazonas - UFAM, 69077-000 Manaus, AM, Brazil.
Eur J Med Chem. 2009 Jan;44(1):312-21. doi: 10.1016/j.ejmech.2008.02.043. Epub 2008 Mar 12.
Phospholipases A(2) 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 PLA(2) 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 PLA(2) from different sources. Herein, we have studied the kinetic behavior and the capacity of inhibiting edema formation induced by PLA(2) 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 PLA(2). 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 PLA(2).
磷脂酶A(2)是负责水解膜磷脂的酶，膜磷脂水解会释放花生四烯酸，花生四烯酸可作为前列腺素和白三烯等促炎介质的底物。设计磷脂酶A(2)的特异性抑制剂可能有助于开发新型抗炎药物。多羟基酚类化合物，如黄酮类化合物、维生素E、迷迭香酸和马兜铃酸，能够抑制来自不同来源的磷脂酶A(2)。在此，我们研究了从眼镜王蛇毒液中提取的五种不同多羟基酚类化合物（两种酚类衍生物和三种苯乙酮羟基化衍生物）抑制磷脂酶A(2)诱导水肿形成的动力学行为和能力。结果表明，间苯二酚、间苯三酚和2,4,6-三羟基苯乙酮在抑制磷脂酶A(2)的酶活性和水肿诱导方面最为有效。还证实了每个分子中羟基的数量不是这些化合物抑制能力的限制因素。分子模拟研究表明，最具活性的化合物与氨基酸天冬氨酸49相连，并且它们会破坏对催化活性至关重要的钙原子的配位。势能表面研究表明，存在一些条件，在这些条件下，势能值必须足以与多羟基酚类化合物形成酶复合物。当羟基表面的势能非常高时，不会形成稳定的复合物，酶也不会强烈起作用。这些结果可能有助于设计一种特异性抑制磷脂酶A(2)的药物。
