Planta Med 2019; 85(18): 1524
DOI: 10.1055/s-0039-3400021
Main Congress Poster
Poster Session 2
© Georg Thieme Verlag KG Stuttgart · New York

Computational investigation of multi-target effects in the arachidonic acid cascade on the example of potent natural 5-LO inhibitor garcinoic acid

V Temml
1   Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck,, Innsbruck, Austria
,
H Pein
2   Chair of Pharmaceutical/Medicinal Chemistry, Friedrich Schiller University Jena,, Jena, Germany
,
S Pace
2   Chair of Pharmaceutical/Medicinal Chemistry, Friedrich Schiller University Jena,, Jena, Germany
,
U Garscha
2   Chair of Pharmaceutical/Medicinal Chemistry, Friedrich Schiller University Jena,, Jena, Germany
,
B Waltenberger
1   Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck,, Innsbruck, Austria
,
F Roviezzo
3   Department of Pharmacy, School of Medicine, University of Naples Federico II,, Naples, Italy
,
JJ Helesbeux
4   Faculty of Health Sciences, Department of Pharmacy, SONAS, EA921, UNIV Angers, SFR QUASAV,, 16 bd Daviers, 49045 Angers Cedex 01, France
,
D Séraphin
4   Faculty of Health Sciences, Department of Pharmacy, SONAS, EA921, UNIV Angers, SFR QUASAV,, 16 bd Daviers, 49045 Angers Cedex 01, France
,
A Rossi
3   Department of Pharmacy, School of Medicine, University of Naples Federico II,, Naples, Italy
,
S Lorkowski
5   Chair of Nutritional Biochemistry and Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena,, Jena, Germany
,
P Richomme
4   Faculty of Health Sciences, Department of Pharmacy, SONAS, EA921, UNIV Angers, SFR QUASAV,, 16 bd Daviers, 49045 Angers Cedex 01, France
,
O Werz
2   Chair of Pharmaceutical/Medicinal Chemistry, Friedrich Schiller University Jena,, Jena, Germany
,
A Koeberle
2   Chair of Pharmaceutical/Medicinal Chemistry, Friedrich Schiller University Jena,, Jena, Germany
,
D Schuster
6   Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Paracelsus Medical University Salzburg,, Salzburg, Austria
,
H Stuppner
1   Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck,, Innsbruck, Austria
› Author Affiliations
Further Information

Publication History

Publication Date:
20 December 2019 (online)

 

Background Secondary plant metabolites often exert their effects by affecting not only one primary target but by interacting with a network of related proteins. The arachidonic acid (AA) cascade is a key pathway in inflammation, which metabolizes AA to a variety of pro and anti-inflammatory mediators. Due to the similarity of the lipid mediator substrates in the pathway, many involved enzymes share common features in their binding sites, and dual or multiple inhibition of the AA cascade is not uncommon [1].

Aims: This work aims to elucidate the similarities between the binding pockets of several AA cascade enzymes, showing why multi-target interaction among these targets is prevalent in many anti-inflammatory natural products. For this purpose, garcinoic acid, a derivative of vitamin E was docked into the enzyme structures from the AA cascade to investigate common binding patterns. Garcinoic acid inhibits 5-lipoxygenase in the nanomolar range (IC50 = 35 nM) and also shows weaker effect on other investigated enzymes: cyclooxygenase 1 in human platelets, IC50 = 6.9 µM, human recombinant leukotriene C4 synthase synthase, IC50 = 9.9 µM, and microsomal prostaglandin E2 synthase, IC50 = 8.8 µM [2].

Results Docking studies revealed an alternative binding site on 5-LO, which was shown to be similar to the binding site of mPGES-1. Overlapping binding site interaction patterns could also be identified with LTC4S.

Conclusion Multi-target effects on related enzymes can be computationally rationalized by binding site comparison, giving us the tools to anticipate such effects and to intentionally search favourable target combinations.

 

  • References

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