Abstract
We investigated the potential role of apple phenolic compounds in human pathologies by integrating chemical characterization of phenolic compounds in three apple varieties, computational approaches to identify potential protein targets of the compounds, bioinformatics analyses on data from public archive of gene expression data, and functional analyses to hypothesize the effects of the selected compounds in molecular pathways. Starting by the analytic characterization of phenolic compounds in three apple varieties, i.e. Annurca, Red Delicious, and Golden Delicious, we used computational approaches to verify by reverse docking the potential protein targets of the identified compounds. Direct docking validation of the potential protein-ligand interactions has generated a short list of human proteins potentially bound by the apple phenolic compounds. By considering the known chemo-preventive role of apple antioxidants’ extracts against some human pathologies, we performed a functional analysis by comparison with experimental gene expression data and interaction networks, obtained from public repositories. The results suggest the hypothesis that chemo-preventive effects of apple extracts in human pathologies, in particular for colorectal cancer, may be the interference with the activity of nucleotide metabolism and methylation enzymes, similarly to some classes of anticancer drugs.
Highlights
Against colorectal cancer[7,8,9,10]
We describe our work based on the integration of: i) analytic approaches to characterize in detail the content of phenolic compounds in the Annurca and in other two very common apple varieties, namely Red Delicious and Golden Delicious; ii) computational approaches to verify by reverse docking the potential protein targets of these phenolic compounds; iii) direct docking validation of the potential protein-ligand interactions with selected targets; iv) comparison with experimental high-throughput studies and investigations of the biological networks that involve the best protein candidates to be interactors of apple polyphenols, by bioinformatics tools
Apple extracts were prepared from three different varieties, Annurca, Red Delicious and Golden Delicious, and their total polyphenolic contents were measured by Folin–Ciocalteau’s method
Summary
Identification and quantification of polyphenols in the apple extracts. Apple extracts were prepared from three different varieties, Annurca, Red Delicious and Golden Delicious, and their total polyphenolic contents were measured by Folin–Ciocalteau’s method. An exception is the interaction between cyanidin-3-galactoside and the proteins GTP-binding nuclear protein Ran (PDB code: 2MMC) and GTP-ase Kras (PDB code: 4OBE) In both cases the interaction in a binding site alternative to the canonical one has a predicted binding energy better than the one associated to the interaction identified with a docking focused on the binding site of the protein (Supplementary Table 2). When the target proteins selected by idTarget have a cofactor bound into the active site, it is possible to note that most antioxidant molecules bind to them with a high affinity only when cofactors are not included in the binding pocket. In the case of GDP bound to protein GTP-ase Kras (PDB code: 4OBE), the water molecules present in the binding site were left in the structure to allow the correct interaction of the cofactor with the protein. Total polyphenols (by Folin-Ciocalteu’s method) GAE Chlorogenic acid p-Coumaroylquinic acid Total hydroxycinnamic acids [+]-Catechin [−]-Epicatechin Total flavanols Procyanidin B1 Procyanidin trimer Procianidin B2 Procyanidin trimer (isomer) Total procyanidins Cyanidin-3-O-galactoside Total anthocyanins Rutin (Quercetin-3-O-rutinoside) Hyperin (Quercetin-3-O-galactoside) Isoquercitrin (Quercetin-3-O-glucoside) Reynoutrin (Quercetin-3-O-xyloside) Guajaverin (Quercetin 3-O-arabinopyranoside) Avicularin (Quercetin 3-O-arabinofuranoside) Quercetin-O-pentoside Quercitrin (Quercetin-3-O-rhamnoside) Total flavonols Phloretin-2-O-xyloglucoside Phloridzin (phloretin-2-O-glucoside) Total dihydrochalcones Total polyphenols (by HPLC method)
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