Abstract
St. John’s Wort (Hypericum perforatum 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 Hypericum 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 H. perforatum extracts containing hypericin and related compounds; and (ii) a rational-based prioritization of H. perforatum components to further characterize their actual effectiveness as anti-inflammatory agents.
Highlights
This work focused on the JH1 domain of JAK1, taken as a reference for the JAK family
The present work dealt with the early mechanistic analysis of Hyp and related compounds to elucidate possible mechanisms underlying their anti-inflammatory action, which has been found a promising ancillary activity along with the antiviral, antibacterial, and antitumor properties
The molecular modeling study showed that Hyp and some analogues are likely to directly contact and possibly inhibit JAK1 providing: (i) a mechanistic rationale explaining, at least in part, the anti-inflammatory activity of H. perforatum extracts pointing to the likely inhibition of JAK1 by Hyp and some analogues; and (ii) an evidence-based top-ranking of JAKs as high-priority candidate for further characterization studies toward a more informed pharmacology of Hyp and other H. perforatum components
Summary
H. perforatum flowers are used to produce oils to treat topical inflammations [7] and the anti-inflammatory activity of extracts of various Hypericum species administered per os was described in animals [8,9,10,11]. A consensus has been achieved neither on the molecular mechanisms nor on the network of molecular targets involved in the anti-inflammatory activity, though critical for a more informed pharmacology of H. perforatum extracts and components thereof. In this regard, H. perforatum extracts typically include complex phytochemical mixtures and the pharmacologically relevant components still lack an adequate molecular profiling and characterization [12]
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