title: Molecular dynamics simulation study and hybrid pharmacophore model development in human LTA4H inhibitor design.
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.
authors.affiliation: Division of Applied Life Science, BK21 Program, Systems and Synthetic Agrobiotech Center, Research Institute of Natural Science, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Sundarapandian
authors.initials: S
authors.lastname: Thangapandian
authors.forename: Shalini
authors.initials: S
authors.lastname: John
authors.forename: Mahreen
authors.initials: M
authors.lastname: Arooj
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011759:Pyrrolidines / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D013876:Thiophenes; C051763:thiophene A; D004851:Epoxide Hydrolases; C032519:pyrrolidine; C043134:leukotriene A4 hydrolase