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

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.

A Structural Study on the Listeria Monocytogenes Internalin A—Human E-cadherin Interaction: A Molecular Tool to Investigate the Effects of Missense Mutations

“…Each InlA-Ecad complex underwent molecular dynamic simulations to assess the possible effects of mutations on the geometrical stability of InlA-Ecad interaction over the time. The overall analysis of complex stability relied on the root-mean-square deviation (RMSD) analysis of protein C-alpha, while the root-mean-square fluctuation (RMSF) analysis of protein C-alpha was performed to locally measure the mobility of protein residues, in agreement with previous studies [27]. According to the results of RMSD and RMSF analysis, there were no appreciable differences among the mutated variants and the wt complex, as, in all the cases analyzed here, each complex kept stable its overall geometry regardless of the mutation hold.…”

Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study

“…Additionally, since GOLD implements a genetic algorithm that may induce variability in the results, all analyses were done in quintuplicate to exclude non-causative scores assignment. Possible outliers were removed to a maximum of one for each run after being identified with the modified Thompson Tau test, as previously reported (Dellafiora et al 2018a). In addition, molecules showing a coefficient of variation higher than 20% were considered unable to find a stable binding architecture.…”

Molecular Modeling of µ Opioid Receptor Ligands with Various Functional Properties: PZM21, SR-17018, Morphine, and Fentanyl—Simulated Interaction Patterns Confronted with Experimental Data

“…In silico methods support the design and development of new drugs at different levels, starting from searching for drug candidates, via optimization of their activity and physicochemical properties, to support in the analysis of their efficiency after introduction to the market [ 7 , 8 , 9 ]. Computational approaches also help in understanding the mechanisms of compound action and simulate processes occurring during receptor activation [ 10 , 11 , 12 ].…”