Article ; Online: Identification of selective 5-LOX and FLAP inhibitors as novel anti-inflammatory agents by ligand-based virtual screening.
European journal of medicinal chemistry
2023 Volume 263, Page(s) 115932
Abstract: Inflammation is a multifaceted biological process in which the conversion of arachidonic acid to eicosanoids, including prostaglandins and leukotrienes (LTs), plays a crucial role. 5-Lipoxygenase (5-LOX) is a key enzyme in cellular LT biosynthesis, and ... ...
| Abstract | Inflammation is a multifaceted biological process in which the conversion of arachidonic acid to eicosanoids, including prostaglandins and leukotrienes (LTs), plays a crucial role. 5-Lipoxygenase (5-LOX) is a key enzyme in cellular LT biosynthesis, and it is supported by the accessory protein 5-lipoxygenase-activating protein (FLAP). Pharmacological interventions to modulate LTs aim at either decreasing their biosynthesis or at mitigating their biological effects. Therefore, inhibiting 5-LOX or FLAP represents a useful strategy to reduce inflammation. Herein we present the identification and pharmacological evaluation of novel inhibitors targeting 5-LOX or FLAP. By means of a ligand-based virtual screening approach, we selected 38 compounds for in vitro assays. Among them, ALR-38 exhibits direct 5-LOX inhibition, while ALR-6 and ALR-27 showed potential as FLAP inhibitors. These latter not only reduced LT production but also promoted the generation of specialized pro-resolving mediators in specific human macrophage phenotypes. Interestingly, the identified compounds turned out to be selective for their respective targets, as none of them displayed activity towards microsomal prostaglandin E |
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| MeSH term(s) | Humans ; 5-Lipoxygenase-Activating Protein Inhibitors/pharmacology ; Ligands ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; Inflammation/drug therapy ; Inflammation/metabolism ; Leukotrienes/metabolism ; Arachidonate 5-Lipoxygenase/metabolism ; Lipoxygenase Inhibitors/pharmacology ; Lipoxygenase Inhibitors/therapeutic use | |||||
| Chemical Substances | 5-Lipoxygenase-Activating Protein Inhibitors ; Ligands ; Anti-Inflammatory Agents ; Leukotrienes ; Arachidonate 5-Lipoxygenase (EC 1.13.11.34) ; Lipoxygenase Inhibitors | |||||
| Language | English | |||||
| Publishing date | 2023-11-08 | |||||
| Publishing country | France | |||||
| Document type | Journal Article | |||||
| ZDB-ID | 188597-2 | |||||
| ISSN | 1768-3254 ; 0009-4374 ; 0223-5234 | |||||
| ISSN (online) | 1768-3254 | |||||
| ISSN | 0009-4374 ; 0223-5234 | |||||
| DOI | 10.1016/j.ejmech.2023.115932 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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