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  2. Identification of selective 5-LOX and FLAP inhibitors as novel anti-inflammatory agents by ligand-based virtual screening

Identification of selective 5-LOX and FLAP inhibitors as novel anti-inflammatory agents by ligand-based virtual screening

  • Eur J Med Chem. 2023 Nov 8:263:115932. doi: 10.1016/j.ejmech.2023.115932.
Carmen Cerchia 1 Laura Küfner 2 Oliver Werz 3 Antonio Lavecchia 4
Affiliations

Affiliations

  • 1 Department of Pharmacy, "Drug Discovery" Laboratory, University of Naples "Federico II", Via D. Montesano 49, 80131, Napoli, Italy.
  • 2 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743, Jena, Germany.
  • 3 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743, Jena, Germany. Electronic address: oliver.werz@uni-jena.de.
  • 4 Department of Pharmacy, "Drug Discovery" Laboratory, University of Naples "Federico II", Via D. Montesano 49, 80131, Napoli, Italy. Electronic address: antonio.lavecchia@unina.it.
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 E2 synthase-1 and soluble Epoxide Hydrolase, which are other proteins involved in eicosanoid biosynthesis. Thus, these compounds are endowed with potential therapeutic utility in mitigating inflammatory responses and might offer a venue for tackling inflammation-based disorders.

Keywords

5-Lipoxygenase (5-LOX); 5-Lipoxygenase-activating protein (FLAP); Drug discovery; Inflammation; Inhibitors; Virtual screening.

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