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Mechanism of inhibition of human secretory phospholipase A2 by flavonoids: rationale for lead design

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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.

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Abbreviations

PLA2:

Phospholipase A2

PLA2-IB:

Phospholipase A2 group IB

PLA2-IIA:

Phospholipase A2 group IIA

3D:

Three-dimensional

MD:

Molecular dynamics

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Acknowledgments

This work has been funded by European Structural Funds (EFRE). MTP group is funded by the Klaus Tschira Stiftung GmbH. We are grateful to Mrs. Mandy Erlitz for her invaluable administrative support.

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Authors and Affiliations

  1. Structural Bioinformatics, BIOTEC TU Dresden, Tatzberg 47-51, 01307, Dresden, Germany

    Jens Lättig & M. Teresa Pisabarro

  2. Institut für Zoologie, TU Dresden, 01062, Dresden, Germany

    Markus Böhl, Claudia Tietböhl & Herwig O. Gutzeit

  3. Institut für Organische Chemie, TU Dresden, 01062, Dresden, Germany

    Petra Fischer, Sandra Tischer & Peter Metz

  4. Institut für Klinische Chemie und Laboratoriumsmedizin, TU Dresden, 01307, Dresden, Germany

    Mario Menschikowski

Authors
  1. Jens Lättig
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  2. Markus Böhl
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  3. Petra Fischer
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  4. Sandra Tischer
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  5. Claudia Tietböhl
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  7. Herwig O. Gutzeit
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  8. Peter Metz
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  9. M. Teresa Pisabarro
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Correspondence to Jens Lättig or M. Teresa Pisabarro.

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Lättig, J., Böhl, M., Fischer, P. et al. Mechanism of inhibition of human secretory phospholipase A2 by flavonoids: rationale for lead design. J Comput Aided Mol Des 21, 473–483 (2007). https://doi.org/10.1007/s10822-007-9129-8

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  • DOI: https://doi.org/10.1007/s10822-007-9129-8

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