Abstract
Human leukotriene A4 hydrolase (hLTA4H) is a bi-functional enzyme catalyzes the hydrolase and aminopeptidase functions upon the fatty acid and peptide substrates, respectively, utilizing the same but overlapping binding site. Particularly the hydrolase function of this enzyme catalyzes the rate-limiting step of the leukotriene (LT) cascade that converts the LTA4 to LTB4. This product is a potent pro-inflammatory activator of inflammatory responses and thus blocking this conversion provides a valuable means to design anti-inflammatory agents. Four structurally very similar chemical compounds with highly different inhibitory profile towards the hydrolase function of hLTA4H were selected from the literature. Molecular dynamics (MD) simulations of the complexes of hLTA4H with these inhibitors were performed and the results have provided valuable information explaining the reasons for the differences in their biological activities. Binding mode analysis revealed that the additional thiophene moiety of most active inhibitor helps the pyrrolidine moiety to interact the most important R563 and K565 residues. The hLTA4H complexes with the most active compound and substrate were utilized in the development of hybrid pharmacophore models. These developed pharmacophore models were used in screening chemical databases in order to identify lead candidates to design potent hLTA4H inhibitors. Final evaluation based on molecular docking and electronic parameters has identified three compounds of diverse chemical scaffolds as potential leads to be used in novel and potent hLTA4H inhibitor design.
Highlights
A ubiquitously present 64 kDa metal (Zn2+) containing cytosolic human leukotriene A4 hydrolase is a bi-functional enzyme with epoxide hydrolase and aminopeptidase activities utilizing the same Zn present active site [1]
We focused on these results and performed molecular dynamics (MD) simulations of LTA4H and these inhibitor complexes as the results can be used to understand about the essential molecular components to bind the active site of the enzyme with high affinity
2.21 4.32 26.39 22.68 1.23 25.21 22.31 20.24 23.40 22.65 2.17 contributions to the electrostatic energy in the ligand binding. This high electrostatic contribution is because of the interactions between negatively charged carboxylate group of LTA4 and positively charged R563 and K565 residues at the active site
Summary
A ubiquitously present 64 kDa metal (Zn2+) containing cytosolic human leukotriene A4 hydrolase (hLTA4H) is a bi-functional enzyme with epoxide hydrolase and aminopeptidase activities utilizing the same Zn present active site [1]. In the proposed binding mode of LTA4, the substrate, these charged residues formed electrostatic interactions with the carboxylate group of LTA4 These direct electrostatic interactions were observed in the X-ray crystal structures in complex with inhibitors possessing carboxylate group or similar chemotypes [26,27]. The role of these residues as putative carboxylate recognition sites in LTA4H were reported by a site-directed mutagenesis combined with x-ray crystallography and inhibition studies. The insights acquired from the present study may be useful in designing novel LTA4H inhibitors as potent anti-inflammatory agents
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