On the Mechanism of Action of Anti-Inflammatory Activity of Hypericin: An In Silico Study Pointing to the Relevance of Janus Kinases Inhibition

• Published in: Molecules (Basel, Switzerland) Vol. 23; no. 12; p. 3058
• Main Authors: Dellafiora, Luca, Galaverna, Gianni, Cruciani, Gabriele, Dall'Asta, Chiara, Bruni, Renato
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22.11.2018; MDPI
• Subjects: Adenosine; Adenosine Triphosphate - metabolism; Animals; anti-inflammatory activity; Anti-inflammatory agents; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Binding sites; Binding, Competitive; Computer Simulation; Congeners; Cytokines; Dietary supplements; Enzyme inhibitors; Flowers; Hydrogen bonds; Hypericin; hypericin metabolites; Hypericum - chemistry; Hypericum perforatum; in silico pharmacodynamics; Inflammation; Inflammatory response; Janus kinase; janus kinase 1; Janus Kinase 1 - antagonists & inhibitors; Janus Kinase 1 - chemistry; Janus Kinase Inhibitors - chemistry; Janus Kinase Inhibitors - pharmacology; Kinases; Ligands; Metabolites; Modelling; Models, Molecular; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Molecular modelling; Molecular Structure; Perylene - analogs & derivatives; Perylene - chemistry; Perylene - pharmacology; Phosphorylation; Plant Extracts - chemistry; Plant Extracts - pharmacology; Topical application; Hypericum perforatum; janus kinase 1; in silico pharmacodynamics; hypericin metabolites; hypericin; anti-inflammatory activity
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules23123058

St. John's Wort ( L.) flowers are commonly used in ethnomedical preparations with promising outcomes to treat inflammation both per os and by topical application. However, the underlying molecular mechanisms need to be described toward a rational, evidence-based, and reproducible use. For this purpose, the aptitude of the prominent metabolite hypericin was assessed, along with that of its main congeners, to behave as an inhibitor of janus kinase 1, a relevant enzyme in inflammatory response. It was used a molecular modeling approach relying on docking simulations, pharmacophoric modeling, and molecular dynamics to estimate the capability of molecules to interact and persist within the enzyme pocket. Our results highlighted the capability of hypericin, and some of its analogues and metabolites, to behave as ATP-competitive inhibitor providing: (i) a likely mechanistic elucidation of anti-inflammatory activity of extracts containing hypericin and related compounds; and (ii) a rational-based prioritization of components to further characterize their actual effectiveness as anti-inflammatory agents.