## 3 Results and Discussion
### Scaffold 2
#### 3.2.3 ADMET Predictions  
The overall pharmacokinetic risks of the hits obtained after Scaffold 2 replacement were calculated (Figure 9). The hit molecule **48** obtained from Scaffold 2 hopping showed an improved ADMET score relative to that of the known potent co-crystallized ligand (**01**). This selected hit was subjected to all-atom MD simulations and binding free energy calculations. The molecule-level intrinsic clearance (uL/min/mg) in rat or human liver microsomes was also predicted (cf. Figure S4). Several of the compounds obtained from Scaffold 2 hopping exhibited a low ADMET risk score (\(\leq\)8), out of which compound **48** (score of \(\leq\)6) was subjected to MD simulations. However, from the set of compounds from Scaffold 2 hopping, five compounds (**40**, **49**, **50**, **55**, and **58**) exhibited a high predicted overall ADMET risk.  
A thorough and detailed toxicity profile prediction study was conducted to investigate the toxicity profiles of the hit molecules after Scaffold 2 hopping (Figure 10). Several of the hits (**50**, **53**, **54**, **55**, **56**, and **58**) obtained from Scaffold 2 replacement showed lower predicted acute hepatotoxicity through the liver enzyme alanine aminotransferase (SER_ALT) than the known most potent co-crystallized ligand (**01**) (cyan). Only one hit from Scaffold 2 hopping (**54**) exhibited reduced predicted hepatotoxicity through the liver enzyme aspartate aminotransferase (SER_AST) relative to that of the known most potent molecule (**01**) (red). Almost all hits had low predicted mutagenicity risk (gray), except for **48**. Several of the  
Figure 8: Matched molecular pairs obtained from in silico receptor-based Scaffold 2 hopping. Only those molecules that exhibited interactions between the novel Scaffold 2 and FmIH residues are shown here. The unreplaced scaffolds are shown in green and the novel scaffolds after replacement are shown in gray. Pink dashed lines indicate FmIH–ligand polar interactions. Cyan dashed lines represent \(\pi\)–\(\pi\) interactions. The key residues in the FmIH binding pocket are shown (C orange). The key interacting residues are labeled in the figure. Blue N, red O, yellow S.  
Figure 11 shows the predicted hERG toxicity, mutagenicity risk, acute rat toxicity, and Rat TD\({}_{50}\) and Mouse TD\({}_{50}\) values for the hits.  
Figure 10: Toxicity property predictions for all the hit compounds obtained from Scaffold 2 hopping. The wedge plots show the properties for the molecules calculated using machine-learning ADMET PredictorTM10.3.0.7 models. Cross-hatched wedges indicate the predictions for out-of-score molecules. **00** is the negative control used in this work.  
Figure 9: Overall risks and ADMET risk scores of all the hit molecules obtained from Scaffold 2 hopping. The wedge plots represent the predicted overall risks, which comprise five different scores, distinctly shown in five colors (Tox_risk, Mut_risk, CYP_risk, Absn_risk, and ADMET_risk). Cross-hatched wedges indicate predictions for the out-of-scope molecules. The heat maps next to the wedge plots represent the ADMET_risk score. Green indicates low ADMET_risk and red indicates high ADMET_risk.