Identification of Human Leukotriene A4 Hydrolase Inhibitors Using Structure-Based Pharmacophore Modeling and Molecular Docking
| Autor: | Qosay Al-Balas, Amanda C. Bryant-Friedrich, Buthina A. Al-Oudat, Suaad A. Audat, Nizar A. Al-Shar’i, Mel F. Bedi, Aref Zayed |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Leukotriene B4
Pharmaceutical Science Article Analytical Chemistry Leukotriene-A4 hydrolase lcsh:QD241-441 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine lcsh:Organic chemistry Catalytic Domain Neoplasms Drug Discovery Humans Physical and Theoretical Chemistry Enzyme Inhibitors 030304 developmental biology chemistry.chemical_classification Epoxide Hydrolases Inflammation leukotriene A4 hydrolase 0303 health sciences biology Chemistry moelcular docking Organic Chemistry Active site Biological activity Lipid signaling leukotriene B4 respiratory system anti-cancer and anti-inflammatory agents Epoxide hydrolase activity Molecular Docking Simulation Enzyme Biochemistry Chemistry (miscellaneous) 030220 oncology & carcinogenesis Drug Design biology.protein pharmacophore modeling Molecular Medicine lipids (amino acids peptides and proteins) Pharmacophore |
| Zdroj: | Molecules, Vol 25, Iss 2871, p 2871 (2020) Molecules Volume 25 Issue 12 |
| ISSN: | 1420-3049 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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