## 3 Results and Discussion
A total of 1933 core hoppinged structures were obtained. Hits obtained from LCH were grouped based  
Figure 3: Top hit molecule obtained from ensemble docking-based virtual screening (ZINC ID: ZINC000257313939), IUPAC name: 5-(5-(4-hydroxy-3-methoxyphenyl)-1-(2-hydroxyethyl)-1H-pyrazol-3-yl)benzene-1,2,4-triol. (**A**) 3D structure of the top hit molecule. (**B**) Interactions between the top hit molecule and the p56\({}^{\text{kk}}\) TK protein residues (PDB ID: 1 LKL). (**C,D**) Two viewpoints of the ligand binding site are shown in surface representation. The p56\({}^{\text{kk}}\) TK protein (PDB ID: 1 LKL) is shown in surface representation and colored using the electrostatic potential (red represents an electrostatic potential value of \(-\)0.2 kT/e; blue represents an electrostatic potential value of \(+\)0.2 kT/e). on three categories: overlap score, synthesizability score, and side chain root-mean-square deviation (RMSD) values. The best scored compounds from these three categories were selected as our potential hit compounds. The overall poses of these three hits (**1**-**3**) and the reference molecule complexed with the protein surface are shown in Figure 4B. The IUPAC names of the hits **1**, **2**, and **3** are as follows: **1**\(\equiv\) 5-((2R,3R,45,5R)-4-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-2,5-dimethyltetrahydrohydrofuran-3-yl)benzene-1,2,4-triol; **2**\(\equiv\) 5-(((1R,3R)-1-hydroxy-3-(4-hydroxy-3-methoxyphenoxy)cyclohexyl)methyl)benzene-1,2,4-triol; and **3**\(\equiv\) (1S,2R,3R,5S)-2-hydroxy-1-((4-hydroxy-3-methoxyphenoxy)methyl)-2,5-dimethyl-3-(2,4,5-trihydroxyphenyl)cyclopentan-1-aminium. **Receptor-based core hopping (RCH):** The best-sored docked hit molecule obtained from ensemble docking-based virtual screening (Figure 3A) was used as the reference in receptor-based core hopping (RCH). This reference hit molecule exhibited four hydrogen bonding interactions with the SH2 domain of p56\({}^{\text{k}\text{c}}\) TK. To enhance the interactions exhibited in the protein-hit complexes, a minimum cut-off for the number of hydrogen bonds requirement was set to 5. The top two hits (**4** and **5**) obtained from RCH are shown in Figure 5. We observed that the novel central scaffold obtained after replacement using  
Figure 4: (**A**) Template assignment for scaffold growing in core hopping, CH (core between the pink and purple arrows will undergo hopping). (**B**) The top three hit compounds (**1**–**3**) obtained from ligand-based core hopping (LCH). Green represents the reference molecule (the top hit from ensemble docking-based virtual screening). Purple, yellow, and pink represent the top hit compounds obtained from LCH. The p56\({}^{\text{k}\text{c}}\) TK protein (PDB ID: 1 LKl) is shown in surface representation and colored using the electrostatic potential (red represents an electrostatic potential value of \(-0.2\) kT/e; blue represents an electrostatic potential value of +0.2 kT/e). the core hopping technique can exhibit a significant number of new hydrogen bonding interactions with the receptor. It should be noted that one of the hits from RCH (shown in cyan; Figure 5 left) showed a synthesizability score of 0, indicating that the ease of synthesis of this molecule is a matter of further investigation. The IUPAC names of the hits **4** and **5** are as follows: **4**\(\equiv\) (1R,2R,4R,5R,E)-1-amino-4-hydroxy-2-(4-hydroxy-3-methoxyphenoxy)-5-(2,4,5-trihydroxyyphenyl)-6-thiabicyclo[3.2.1]octan-8-one oximice; and **5**\(\equiv\) 6-(4-hydroxy-3-methoxybenzyl)-2-oxo-N-(2,4,5-trihydroxybenzyl)-2,3-dihydro-1H-thieno[3,4-d]imidazole-1-sulfonamide. **ADMET prediction of the top hit compounds:** The top five compounds obtained from the ligand-based and structure-based design strategy of CH, along with the reference compound obtained from ensemble-based virtual screening, were subjected to in silico ADMET prediction calculations.