A combined molecular docking and molecular structure in silico analysis on the substrate and product of leukotriene A4 hydrolase (LTA4H) was performed. The molecular structures of the substrate leukotriene A4 (LTA4) and product leukotirene B4 (LTB4) were studied through density functional theory (DFT) calculations at the B3LYP ⁄ 6-31 + G(d) level of theory in both gas and condensed phases. The whole LTB4 molecule was divided into three fragments (hydrophobic tail, triene motif, and a polar acidic group) that were subjected to a full conformational study employing the most stable conformations of them to build conformers of the complete molecule and geometry optimize further. LTA4 conformers' structures were modeled from the LTB4 minimum energy conformers. Both protonated and deprotonated species of LTA4 and LTB4 were analyzed according to pKa values found in the literature. Finally, a binding model of LTA4 with LTA4 hydrolase is proposed according to docking results that show intermolecular interactions that position the protonated and deprotonated ligand in the active site, in excellent agreement with the model suggested from LTA4H-inhibitors crystallographic data.Key words: binding, leukotriene A4 hydrolase, leukotrienes, molecular docking, molecular structure Received 3 April 2012, revised 12 July 2012 and accepted for publication 17 August 2012Leukotrienes (LTs) constitute a family of endogenous metabolites of arachidonic acid that are biosynthesized via the lipoxygenase pathway (1-3). These interesting compounds are a class of lipid mediators involved in the development and maintenance of inflammatory and allergic reactions (4-7). Leukotriene A4 (LTA4), an unstable alkyl epoxide formed from the immediate precursor 5-HPETE via 5-lipoxygenase (5-LO) (8), is converted to leukotriene B4 (5S,12R-dihydroxy-6Z,8E,10E,14Z-eicosatetraenoicacid; LTB4; Figure 1), by stereoselective hydratation of LTA4 hydrolase (LTA4H) (9). LTB4 is a potent proinflammatory mediator implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD), psoriasis, rheumatoid arthritis, and asthma and plays an important role in immunological responses, chronic obstructive pulmonary disease (COPD), and atherosclerosis (4,6,10-12).On the other hand, LTA4H is a bifunctional zinc metalloenzyme that catalyzes the rate-limiting step in the production of LTB4 (13). The X-ray crystal structures of LTA4H in complex with different inhibitors have been obtained by several authors (14-16). According to several investigations, the metal site is located next to the putative active site bound to His295, His299,.In this study, we show an analysis of the different interactions of LTA4 into LTA4H through molecular docking study. Molecular and electronic structure information of LTA4 and LTB4, obtained from an exhaustive conformational analysis, was used to set an initial conformation for the docking study.There are few theoretical studies about the molecular structure of LTB4. One of them was performed by Brasseur et al. (19) ...

The leukotriene A4 hydrolase (LTA4H) is a bifunctional zinc enzyme that catalyzes the final (ratelimiting) step in the synthesis of leukotriene B4 (LTB4), which is involved in several diseases. Many pharmaceutical attempts to exploit the LTA4H/LTB4 pathway have been unsatisfactory, hence, the development of new inhibitory drugs is essential. This paper describes the generation of a quantitative structure-activity relationship (QSAR) model on a series of 50 N-alkyl glycine amides with experimentally defined IC 50 . In addition, the optimized molecular structures of the inhibitors were docked into the active site of the enzyme to identify the enzymeligand interactions and quantify the estimated free energy of binding (DG bind ). A simple four-descriptor QSAR model with high predictive capacity was obtained. The statistic parameters of the model are: regression coefficient (R test ) of 0.714 and a standard deviation (S test ) of 0.696. The predicted inhibitory activity of 85 new N-alkyl glycine amides compounds was obtained with this QSAR model and these compounds were docked into LTA4H. Ten of the compounds present predicted IC 50 values lower than 10 nM and binding poses and affinity values similar to the natural ligand (leukotriene A4), turning them into suitable candidates for experimental assays.

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