Discovery of Novel 5-lox Inhibitors: Pharmacophore Design, Homology and Docking Studies

Abstract

Inhibition of leukotriene biosynthesis has been extensively studied as a potential for the development of novel therapies for inflammation, respiratory diseases and, in particular, for asthma. We have designed specific functional inhibitors against 5-Lipoxygenase (5-LOX) using several virtual screening techniques like Homology modeling, MD simulations, Docking and Pharmacophore studies. We have identified 6 analogues of novel 5-LOX inhibitors (IC50 < 19 nM) using pharmacophore models and docking studies and their drug like properties were evaluated. These 6 compounds can be taken for further study including synthesis. 5-LOX (5- Lipoxygenase) was found to be a cytosolic enzyme and contained a non-heme iron atom and calcium. This iron atom is critical to determine the catalytic potential of the enzyme, with oxidation to the ferric (Fe3+) form conferring activity (1). 5-LOX can be activated by an increase in intracellular Ca2+ concentration, diacylglycerols, phosphorylation by MAPKAP (mitogen-activated protein kinase-activated protein kinase) kinase-2 and ERK (Extracellular Receptor Kinase) (2). In the absence of calcium, 5-LOX has minimal catalytic activity. The addition of calcium stimulates both the oxygenation and dehydration reactions of 5-LOX. This enzyme is expressed mainly in leukocytes, in line with the function of leukotrienes as mediators of immune reactions (3). Granulocytes, monocytes/macrophages, mast cells, dendritic cells and B lymphocytes express 5-LOX, whereas platelets, endothelial cells, T cells and erythrocytes do not. 5-lipoxygenase (5- LOX) catalyzes the first two steps in the synthesis of all LTs (Leukotriene's), namely the oxidation of AA to 5- hydroperoxyeicosatetraenoic acid (5HPETE) followed by the dehydration of 5-HPETE to LTA (4). 5-Lipoxygenase has a central role in the biosynthesis of leukotrienes. This enzyme initializes the formation of proinflammatory leukotrienes from arachidonic acid (AA). The potent biological effects of Leukotriene's (LTs) includes leukocyte