## 3 Results and Discussion
### Scaffold 1
#### 3.1.3 ADMET Predictions  
The overall pharmacokinetic risks of the hits obtained after Scaffold 1 replacement were calculated (Figure 5). An ADMET Predictor risk score ranges between 0-22, and indicates the number of potential ADMET problems that a compound might have: Absorption contributes up to 8 points; Distribution up to 2 points; CYP metabolism up to 6 points; and Toxicity up to 6 points. A cut-off of the ADMET risk score of \(\leq\)6 was used to select the hit compounds with a significantly low ADMET risk (**01**, **03**, **2**, **5**, **9**, and **24**). **01** and **03** are  
Figure 4: Matched molecular pairs obtained from in silico receptor-based Scaffold 1 hopping. Only those molecules are shown here that exhibited interactions between the novel Scaffold 1 and FmIH residues. The unreplaced scaffolds are shown with green carbons and the novel scaffolds after replacement are shown with gray carbons. 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 (with orange carbons). The key interacting residues are labeled in the figure.  
the most potent co-crystallized ligand [18] and a hit molecule identified in our previously reported in silico study [14], respectively. The selected hits from Scaffold 1 hopping that exhibited improved ADMET scores were subjected to all-atom MD simulations and binding free energy calculations. The molecule-level intrinsic clearance (uL/min/mg) for human (HLM) and rat (RLM) liver microsomes were predicted and are shown in Figure S3.  
To investigate the toxicity profiles of the hit compounds, we performed a thorough and detailed toxicity profile prediction study (Figure 6). Most hits obtained from Scaffold 1 replacement showed lower predicted acute hepatotoxicity through the liver enzyme alanine aminotransferase (SER_ALT) than the known most potent co-crystallized ligand (**01**) (cyan). However, most compounds showed similar predicted hepatotoxicity through the liver enzyme aspartate aminotransferase (SER_AST) to that of **01** (red). Almost all the hits had a low predicted mutagenicity risk (gray), similar to **01**. Nineteen of the hit compounds (**03**, **04**, **5**, **7**, **9**, **10**, **13**, **14**, **18**, **19**, **23**, **26**, **27**, **28**, **29**, **30**, **31**, **34**, and **35**) showed lower hERG_pIC\({}_{50}\) than **01** (green).  
Figure 5: Overall risks and ADMET risk scores of all the hit molecules obtained from Scaffold 1 hopping. The wedge plots represent the predicted overall risks, which are comprised of 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 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.  
Figure 6: Toxicity property predictions for all the hit compounds obtained from Scaffold 1 hopping. The wedge plots show properties for the molecules calculated using machine-learning ADMET PredictorTM10.3.0.7 models. Cross-hatched wedges indicate predictions for out-of-scope molecules. The different colored wedges represent the various toxicity properties, which are indicated in the figure labels.