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. 2022 Apr 26;11(9):1253.
doi: 10.3390/foods11091253.

Inverse Molecular Docking Elucidating the Anticarcinogenic Potential of the Hop Natural Product Xanthohumol and Its Metabolites

Katarina Kores  1 , Zala Kolenc  1 , Veronika Furlan  1 , Urban Bren  1   2
Affiliations

Inverse Molecular Docking Elucidating the Anticarcinogenic Potential of the Hop Natural Product Xanthohumol and Its Metabolites

Katarina Kores et al. Foods. .

Abstract

Natural products from plants exert a promising potential to act as antioxidants, antimicrobials, anti-inflammatory, and anticarcinogenic agents. Xanthohumol, a natural compound from hops, is indeed known for its anticarcinogenic properties. Xanthohumol is converted into three metabolites: isoxanthohumol (non-enzymatically) as well as 8- and 6-prenylnaringenin (enzymatically). An inverse molecular docking approach was applied to xanthohumol and its three metabolites to discern their potential protein targets. The aim of our study was to disclose the potential protein targets of xanthohumol and its metabolites in order to expound on the potential anticarcinogenic mechanisms of xanthohumol based on the found target proteins. The investigated compounds were docked into the predicted binding sites of all human protein structures from the Protein Data Bank, and the best docking poses were examined. Top scoring human protein targets with successfully docked compounds were identified, and their experimental connection with the anticarcinogenic function or cancer was investigated. The obtained results were carefully checked against the existing experimental findings from the scientific literature as well as further validated using retrospective metrics. More than half of the human protein targets of xanthohumol with the highest docking scores have already been connected with the anticarcinogenic function, and four of them (including two important representatives of the matrix metalloproteinase family, MMP-2 and MMP-9) also have a known experimental correlation with xanthohumol. Another important protein target is acyl-protein thioesterase 2, to which xanthohumol, isoxanthohumol, and 6-prenylnaringenin were successfully docked with the lowest docking scores. Moreover, the results for the metabolites show that their most promising protein targets are connected with the anticarcinogenic function as well. We firmly believe that our study can help to elucidate the anticarcinogenic mechanisms of xanthohumol and its metabolites as after consumption, all four compounds can be simultaneously present in the organism.

Keywords: anticarcinogenic effects; inverse molecular docking; metabolites; xanthohumol.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Chemical structures of compounds: (A) xanthohumol, (B) isoxanthohumol, (C) 8-prenylnaringenin, and (D) 6-prenylnaringenin.
Figure 2
Figure 2
The workflow of the protein target prediction approach. Using inverse molecular docking, xanthohumol was docked into target human proteins from the Protein Data Bank (PDB) with predicted binding sites from the ProBiS-Dock database. Inverse molecular docking was performed with the CANDOCK algorithm.
Figure 3
Figure 3
Normal distribution fitting graphs of inverse docking scores for xanthohumol, isoxanthohumol, 8-prenylnaringenin, and 6-prenylnaringenin. 3σ is the designation for 99.7% confidence interval, and the N represents the number of proteins that fit these preselected criteria.
Figure 4
Figure 4
Analysis of interactions between the binding site of matrix metalloproteinase 9 (blue) and the docked xanthohumol (orange). Hydrogen bonds are depicted with blue lines, water bridges with light purple, and hydrophobic interactions with gray.
Figure 5
Figure 5
Comparison of the docked xanthohumol (gray), isoxanthohumol (purple), and 6-prenylnaringenin (green) to the acyl-protein thioesterase 2 (PDB ID 5syn). All docked molecules lie within the same binding pocket. The protein is depicted in a blue cartoon model.
Figure 6
Figure 6
Analysis of interactions between the binding site of acyl-protein thioesterase 2 (blue) and (A) xanthohumol (gray), (B) isoxanthohumol (purple), and (C) 6-prenylnaringenin (green). Hydrogen bonds are represented by blue lines, water bridges by light purple, π-stacking by green, and hydrophobic interactions by gray.
Figure 7
Figure 7
Validation of the inverse molecular docking protocol of xanthohumol against all human protein targets from the Protein Date Bank (PDB): (A) the receiver operating characteristics (ROC) curve; (B) the predictiveness curve; and (C) the enrichment curve.
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