Identification of Human Leukotriene A4 Hydrolase Inhibitors Using Structure-Based Pharmacophore Modeling and Molecular Docking

Abstract

Leukotriene B4 (LTB4) is a potent, proinflammatory lipid mediator implicated in the pathologies of an array of inflammatory diseases and cancer. The biosynthesis of LTB4 is regulated by the leukotriene A4 hydrolase (LTA4H). Compounds capable of limiting the formation of LTB4, through selective inhibition of LTA4H, are expected to provide potent anti-inflammatory and anti-cancer agents. The aim of the current study is to obtain potential LTA4H inhibitors using computer-aided drug design. A hybrid 3D structure-based pharmacophore model was generated based on the crystal structure of LTA4H in complex with bestatin. The generated pharmacophore was used in a virtual screen of the Maybridge database. The retrieved hits were extensively filtered, then docked into the active site of the enzyme. Finally, they were consensually scored to yield five hits as potential LTA4H inhibitors. Consequently, the selected hits were purchased and their biological activity assessed in vitro against the epoxide hydrolase activity of LTA4H. The results were very promising, with the most active compound showing 73.6% inhibition of the basal epoxide hydrolase activity of LTA4H. The results from this exploratory study provide valuable information for the design and development of more potent and selective inhibitors.

Current Status of the Use of Multifunctional Enzymes as Anti-Cancer Drug Targets

“…In the last stage of the study, they experimentally evaluated the epoxide hydrolase inhibitory activities of the five best scored hits found in silico. Among the tested compounds, the one designated RH00633 (Figure 12) stands out with 73.6% inhibition of the basal epoxide hydrolase activity of LTA 4 H. RH00633 binds to the enzyme's active site and interacts with the catalytic Zn2+, along with several other important catalytic residues [112].…”

“…The current status of the development of inhibitors targeting the four enzymes described in this review is summarized in Table 1. 3PO [46] yes [46] yes [46] no PFK15 [48] yes [48] yes [48] no PFK158 [48] yes [49] yes [49] NCT02044861 [50] PFK-2 activity of PFKFB4 5MPN [51] yes [51] yes [51] no ATIC AICAR TFase BW1540 [57] no no no AICAR TFase BW2315 [57] no no no AICAR TFase LSN3213128 [66] yes [66,67] yes [66,67] no LTA 4 H epoxide hydrolase and aminopeptidase activities Acebilustat no available data no available data no (1) epoxide hydrolase and aminopeptidase LYS006 [105] yes [105] yes [105] no (1) epoxide hydrolase RH00633 [112] yes [112] no no…”

Exploring the Antibacterial Potential of Artemisia judaica Compounds Targeting the Hydrolase/Antibiotic Protein in Klebsiella pneumoniae: In Vitro and In Silico Investigations

“…The receptor proteins’ binding sites were identified using the “receptor cavity technique” in Accelrys Discovery Studio 4.0 [ 42 ]. This study’s method helped identify the target receptor’s active areas.…”

Headspace SPME-GC-MS Analysis and in silico Molecular Docking Studies of Phytochemical Compounds Present in Houttuynia cordata Thunb

“…20 For Anticancer and Anti-inflammatory targets, the binding site grid coordinates were predicted by using BIOVIA Discovery Studio, at first the co-crystallised ligands were selected and the "Define and Edit Binding Site" option was used. 21…”