Abstract
Essential oils (EOs) are popular in aromatherapy, a branch of alternative medicine that claims their curative effects. Moreover, several studies reported EOs as potential anti-cancer agents by inducing apoptosis in different cancer cell models. In this study, we have considered EOs as a potential resource of new kinase inhibitors with a polypharmacological profile. On the other hand, computational methods offer the possibility to predict the theoretical activity profile of ligands, discovering dangerous off-targets and/or synergistic effects due to the potential multi-target action. With this aim, we performed a Structure-Based Virtual Screening (SBVS) against X-ray models of several protein kinases selected from the Protein Data Bank (PDB) by using a chemoinformatics database of EOs. By evaluating theoretical binding affinity, 13 molecules were detected among EOs as new potential kinase inhibitors with a multi-target profile. The two compounds with higher percentages in the EOs were studied more in depth by means Induced Fit Docking (IFD) protocol, in order to better predict their binding modes taking into account also structural changes in the receptor. Finally, given its good binding affinity towards five different kinases, cinnamyl cinnamate was biologically tested on different cell lines with the aim to verify the antiproliferative activity. Thus, this work represents a starting point for the optimization of the most promising EOs structure as kinase inhibitors with multi-target features.
Highlights
Essential oils (EOs), called volatile or ethereal oils, are aromatic, highly volatile, hydrophobic liquids produced by aromatic plants as secondary metabolites
Theoretical studies, based on chemoinformatics and bioinformatics methods, are capable to speed up the identification of bioactive compounds, by testing with in vitro and in vivo assays only the most promising candidates selected through in silico simulations [17,18,19,20,21,22,23]
Excluding the clinical trials, chemoinformatics and bioinformatics play a crucial role in every step of the drug discovery design chemoinformatics and bioinformatics play a crucial role in every step of the drug discovery design chemoinformatics play a[30]
Summary
Essential oils (EOs), called volatile or ethereal oils, are aromatic, highly volatile, hydrophobic liquids produced by aromatic plants as secondary metabolites. Theoretical studies, based on chemoinformatics and bioinformatics methods, are capable to speed up the identification of bioactive compounds, by testing with in vitro and in vivo assays only the most promising candidates selected through in silico simulations [17,18,19,20,21,22,23] In this regard, SBVS is a computational approach useful to identify novel bioactive ligands against a certain target or a set of interesting targets, getting information from the three-dimensional (3D) structures of proteins or nucleic acids, obtained from X-ray or NMR methodologies. Computational techniques may predict in silico the theoretical ligand activities profile versus a set of targets, thereby potential selectivity issues or multi-target activities may be early identified, rationalizing favorable synergic effects or dangerous side ones, caused by drug binding to unwanted off-targets [26,27,28] With this purpose, we performed a SBVS by using a database of EOs bioactive components and a dataset of kinase receptors.
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