## 3 Results
### In Silico Evaluation of Reference Compounds by Docking Simulations  
According to recent data [43], tankyrase 1 (TNKS1) and tankyrase 2 (TNKS2) are two homologous proteins involved in multiple pathological situations, diseases, and cancer development in humans: the two proteins (enzymes) were identified in colon cancer, gastric cancer, bladder cancer, pancreatic cancer, and also breast and brain cancer. On the other hand, human colorectal cancer is the second leading cause of cancer death worldwide [44], and statistical data have revealed that approximately 90% of worldwide human colorectal tumors show the hyper-activation of \(\upbeta\)-catenin signaling pathway, while the TNKS inhibitors were found through the regulation of the limiting factor of the \(\upbeta\)-catenin degradation protein Axin [43]. Moreover, in vitro and in vivo proof-of-concept studies established the profile of the selective inhibitors of TNKS in cancer and tankyrase linked diseases [45]. In this context, studying TNKS inhibitory potential of natural compounds is of great interest. Therefore, molecular docking simulation aimed to study potential inhibitory effects of the five phenolics in the series of food-related bioactive compounds on the molecular targets TNKS1 and TNKS2, compared to the PDB native inhibitors namely Co-crystallized 3]5A and Co-crystallized FLN. * Results of molecular docking study (Table 1) on human tankyrase 1 (PDB ID: 4W6E) have revealed the greatest inhibitory score (\(-\)104.15) for the Co-crystallized 3]5A ligand: four hydrogen bond formations with GLU1291 (x2), SER1221 and GLY1185 amino acid residues (see Supplementary Figure S1) were counted. It is noticed that luteolin-7-O-glucose strongly interacted with SER1221, and GLY1185 by hydrogen bonding and additionally with GLY1196 and ASP1198, achieving a docking score value of \(-\)80.49, the best among the investigated ligands. Except for Luteolin-8-C-glcoside, all molecules interact with GLY1185 and SER1221 (see Supplementary Figures S2-S6), meaning satisfactory docking scores. * Molecular docking simulations on the human tankyrase 2 (PDB ID: 4 HKI) (Table 2) have revealed luteolin-7-O-glucoside the highest inhibiting potency, as suggests its docking score (\(-\)85.17), greater than that obtained for the native PDB ligand FLN (\(-\)76.97); punctually, luteolin-7-O-glucose interacts by eleven hydrogen bonds with the amino acids residues SER1068 and GLY1032 on chain A (see Supplementary Figure S7), and additionally, amino acid GLU1138 on chain C (see Supplementary Figure S8). Furthermore, the results place the other screened ligands in order: caffe acid (\(-\)57.17) > gentisic acid (\(-\)51.66) > p-aminobenzoxic acid (\(-\)50.42) > luteolin-8-C-glcoside (\(-\)43.47); their interactions within the active binding site of tankyrase 2 are given in Supplementary Figures S9-S12. To better identify and depict their interactions within the complexes, in Figure S13, the atomic labeling schemes for investigated structures, as arbitrarily provided by Spartan software upon energy minimization, are given. Table 3 depicts [PERSON]'s parameters for druggability assessment of the two native PDB inhibitors (3]5A and FLN), and of the five phenolics studied (ref.). The data indicate that the major difference between the two native ligands consists in the number of hydrogen bond acceptors (e.g., hydroxyl and amino -groups), HBA = 7 for 3J5 structure and HBA = 2 for FLN structure, partly explaining their significant difference in score's magnitude and inhibition effectiveness.