Leukotriene B4 (LTB4) is a potent, proinflammatory lipid mediator implicated in the\npathologies of an array of inflammatory diseases and cancer. The biosynthesis of LTB4 is regulated\nby the leukotriene A4 hydrolase (LTA4H). Compounds capable of limiting the formation of LTB4,\nthrough selective inhibition of LTA4H, are expected to provide potent anti-inflammatory and\nanti-cancer agents. The aim of the current study is to obtain potential LTA4H inhibitors using\ncomputer-aided drug design. A hybrid 3D structure-based pharmacophore model was generated\nbased on the crystal structure of LTA4H in complex with bestatin. The generated pharmacophore\nwas used in a virtual screen of the Maybridge database. The retrieved hits were extensively filtered,\nthen docked into the active site of the enzyme. Finally, they were consensually scored to yield five hits\nas potential LTA4H inhibitors. Consequently, the selected hits were purchased and their biological\nactivity assessed in vitro against the epoxide hydrolase activity of LTA4H. The results were very\npromising, with the most active compound showing 73.6% inhibition of the basal epoxide hydrolase\nactivity of LTA4H. The results from this exploratory study provide valuable information for the design\nand development of more potent and selective inhibitors.
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