title: Mechanism of inhibition of human secretory phospholipase A2 by flavonoids: rationale for lead design.
abstract: The human secretory phospholipase A2 group IIA (PLA2-IIA) is a lipolytic enzyme. Its inhibition leads to a decrease in eicosanoids levels and, thereby, to reduced inflammation. Therefore, PLA2-IIA is of high pharmacological interest in treatment of chronic diseases such as asthma and rheumatoid arthritis. Quercetin and naringenin, amongst other flavonoids, are known for their anti-inflammatory activity by modulation of enzymes of the arachidonic acid cascade. However, the mechanism by which flavonoids inhibit Phospholipase A2 (PLA2) remained unclear so far. Flavonoids are widely produced in plant tissues and, thereby, suitable targets for pharmaceutical extractions and chemical syntheses. Our work focuses on understanding the binding modes of flavonoids to PLA2, their inhibition mechanism and the rationale to modify them to obtain potent and specific inhibitors. Our computational and experimental studies focused on a set of 24 compounds including natural flavonoids and naringenin-based derivatives. Experimental results on PLA2-inhibition showed good inhibitory activity for quercetin, kaempferol, and galangin, but relatively poor for naringenin. Several naringenin derivatives were synthesized and tested for affinity and inhibitory activity improvement. 6-(1,1-dimethylallyl)naringenin revealed comparable PLA2 inhibition to quercetin-like compounds. We characterized the binding mode of these compounds and the determinants for their affinity, selectivity, and inhibitory potency. Based on our results, we suggest C(6) as the most promising position of the flavonoid scaffold to introduce chemical modifications to improve affinity, selectivity, and inhibition of PLA2-IIA by flavonoids.
authors: Structural Bioinformatics, BIOTEC TU Dresden, Tatzberg 47-51, 01307, Dresden, Germany. jens.laettig@biotec.tu-dresden.de
authors: Jens
authors: J
authors: Lättig
authors: Markus
authors: M
authors: Böhl
authors: Petra
authors: P
authors: Fischer
authors: Sandra
authors: S
authors: Tischer
authors: Claudia
authors: C
authors: Tietböhl
authors: Mario
authors: M
authors: Menschikowski
authors: Herwig O
authors: HO
authors: Gutzeit
authors: Peter
authors: P
authors: Metz
authors: M Teresa
authors: MT
authors: Pisabarro
mesh_terms: D020134:Catalytic Domain; D003198:Computer Simulation; D017076:Computer-Aided Design; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D008024:Ligands; D054497:Phospholipases A2, Secretory
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