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DOI: 10.1055/s-0039-3400021
Computational investigation of multi-target effects in the arachidonic acid cascade on the example of potent natural 5-LO inhibitor garcinoic acid
Publikationsverlauf
Publikationsdatum:
20. Dezember 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.
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References
- 1 Meirer K, Steinhilber D, Proschak E. Inhibitors of the arachidonic acid cascade: interfering with multiple pathways. Basic Clin Pharmacol Toxicol 2014; 114: 83-91
- 2 Pein H, Ville A, Pace S, Temml V, Garscha U, Raasch M. et al. Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. Nat Commun 2018; 9 (01) : 3834
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References
- 1 Meirer K, Steinhilber D, Proschak E. Inhibitors of the arachidonic acid cascade: interfering with multiple pathways. Basic Clin Pharmacol Toxicol 2014; 114: 83-91
- 2 Pein H, Ville A, Pace S, Temml V, Garscha U, Raasch M. et al. Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. Nat Commun 2018; 9 (01) : 3834