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.

Structural Origins for the Loss of Catalytic Activities of Bifunctional Human LTA4H Revealed through Molecular Dynamics Simulations

“…The enzyme 5-lipoxygenase (5-LO) assisted by file-lipoxygenase-activating protein (FLAP) converts the AA into the highly unstable allylic epoxide, leukotriene A4 (LTA4) [15][16][17][18][19][20][21]. This unstable intermediate is converted into two different products LTB4 and LTC4 by the action of two different enzymes LTA4 hydrolase (LTA4H) and LTC4 synthase (LTC4S), respectively [1,[22][23][24][25]. The LTC4 is subsequently converted to LTD4 and LTE4 substances by the action of different enzymes.…”

Molecular dynamics simulation and density functional theory insight into the cocrystal explosive of hexaazaisowurtzitane/nitroguanidine

“…The van der Waals (vdW) and Coulombic are calculated by atom based and Ewald, respectively. All above calculations are executed with the software of Materials Studio 7.0 …”

“…All above calculations are executed with the software of Materials Studio 7.0. [30] On the equilibrium structure of CL-20/NQ, the binding energy (E b ) can well reflect their intermolecular interaction energy (DE) of the two components blending with each other. So the E b between CL-20 and NQ can be defined as follows:…”

QM/MM Molecular Dynamics Investigations of the Substrate Binding of Leucotriene A4 Hydrolase: Implication for the Catalytic Mechanism

“…As shown in Scheme B, the zinc ion could act as a Lewis acid catalyst to activate the epoxy atom with double-hydrogen-atom migration to break the epoxide ring. Subsequently, the production of LTB4 involves charge delocalization over the conjugated triene system (C6–C12). , Some important residues like D375 and Y378 − have been well studied in the functions of catalysis and enantioselectivity. In this work, we will just focus on the substrate binding modes and the first step of ring opening of the epoxide ring as an epoxide hydrolase.…”

“… a (A) One active site water molecule is suggested to be the fourth ligand to the zinc ion. ,, (B) The oxygen atom on epoxy ring B is supposed to be the fourth ligand to the zinc ion. ,, …”