In silico modeling of the molecular structure and binding of leukotriene A4 into leukotriene A4 hydrolase.

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.