Resveratrol is a polyphenol known for its antioxidant and anti-inflammatory properties, which support its use as a treatment for variety of diseases. There are already known connections of resveratrol to chemoprevention of cancer because of its ability to prevent tumor initiation and inhibit tumor promotion and progression. Resveratrol is also believed to be important in cardiovascular diseases and neurological disorders, such as Alzheimer’s disease. Using an inverse molecular docking approach, we sought to find new potential targets of resveratrol. Docking of resveratrol into each ProBiS predicted binding site of >38 000 protein structures from the Protein Data Bank was examined, and a number of novel potential targets into which resveratrol was docked successfully were found. These explain known actions or predict new effects of resveratrol. The results included three human proteins that are already known to bind resveratrol. A majority of proteins discovered however have no already described connections with resveratrol. We report new potential target human proteins and proteins connected with different organisms into which resveratrol can dock. Our results reveal previously unknown potential target human proteins, whose connection with cardiovascular and neurological disorders could lead to new potential treatments for variety of diseases. We believe that our research could help in future experimental studies on revestratol bioactivity in humans.

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Thiazolidinediones form drugs that treat insulin resistance in type 2 diabetes mellitus. Troglitazone represents the first drug from this family, which was removed from use by the FDA due to its hepatotoxicity. As an alternative, rosiglitazone was developed, but it was under the careful watch of FDA for a long time due to suspicion, that it causes cardiovascular diseases, such as heart failure and stroke. We applied a novel inverse molecular docking protocol to discern the potential protein targets of both drugs. Troglitazone and rosiglitazone were docked into predicted binding sites of >67,000 protein structures from the Protein Data Bank and examined. Several new potential protein targets with successfully docked troglitazone and rosiglitazone were identified. The focus was devoted to human proteins so that existing or new potential side effects could be explained or proposed. Certain targets of troglitazone such as 3-oxo-5-beta-steroid 4-dehydrogenase, neutrophil collagenase, stromelysin-1, and VLCAD were pinpointed, which could explain its hepatoxicity, with additional ones indicating that its application could lead to the treatment/development of cancer. Results for rosiglitazone discerned its interaction with members of the matrix metalloproteinase family, which could lead to cancer and neurodegenerative disorders. The concerning cardiovascular side effects of rosiglitazone could also be explained. We firmly believe that our results deepen the mechanistic understanding of the side effects of both drugs, and potentially with further development and research maybe even help to minimize them. On the other hand, the novel inverse molecular docking protocol on the other hand carries the potential to develop into a standard tool to predict possible cross-interactions of drug candidates potentially leading to adverse side effects.

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.

The present study addresses the chemoprotective effects of xanthohumol (XN), a prenylated flavonoid found in the female inflorescences (hops) of the plant Humulus lupulus L., against the carcinogenic food contaminant aflatoxin B1 (AFB1). The chemical reactions of XN and its derivatives (isoxanthohumol (IXN), 8-prenylnaringenin (8-PN), and 6-prenylnaringenin (6-PN)) with the AFB1 metabolite, aflatoxin B1 exo-8,9-epoxide (AFBO), were investigated in silico, by calculating activation free energies (ΔG⧧) at the Hartree–Fock level of theory in combination with the 6-311++G(d,p) basis set and two implicit solvation models. The chemoprotective effects of XN were investigated in vitro in the metabolically competent HepG2 cell line, analyzing its influence on AFB1-induced cytotoxicity using the MTS assay, genotoxicity using the comet and γH2AX assays, and cell cycle modulation using flow cytometry. Our results show that the ΔG⧧ required for the reactions of XN and its derivatives with AFBO are comparable to the ΔG⧧ required for the reaction of AFBO with guanine, indicating that XN, IXN, 8-PN, and 6-PN could act as scavengers of AFBO, preventing DNA adduct formation and DNA damage induction. This was also reflected in the results from the in vitro experiments, where a reduction in AFB1-induced cytotoxicity and DNA single-strand and double-strand breaks was observed in cells exposed to combinations of AFB1 and XN, highlighting the chemoprotective effects of this phytochemical.