Mechanism of inhibition of human secretory phospholipase A2 by flavonoids: rationale for lead design |
| |
Authors: | Jens Lättig Markus Böhl Petra Fischer Sandra Tischer Claudia Tietböhl Mario Menschikowski Herwig O Gutzeit Peter Metz M Teresa Pisabarro |
| |
Institution: | (1) Structural Bioinformatics, BIOTEC TU Dresden, Tatzberg 47-51, 01307 Dresden, Germany;(2) Institut für Zoologie, TU Dresden, 01062 Dresden, Germany;(3) Institut für Organische Chemie, TU Dresden, 01062 Dresden, Germany;(4) Institut für Klinische Chemie und Laboratoriumsmedizin, TU Dresden, 01307 Dresden, Germany |
| |
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. |
| |
Keywords: | Phospholipase A2 PLA2 Inhibitor Rational design Flavonoid Quercetin Naringenin |
本文献已被 PubMed SpringerLink 等数据库收录! |
|