## 3 Results and Discussion
### Binding Free Energy Calculations from the MD Simulations
Additionally, it is predicted to have high hERG toxicity (Figure 10, green and Figure 11A) and some mutagenicity risk (Figure 11A). It is important to note that small molecule drug discovery is a multi-parameter optimization problem, with the aim of identifying high-quality compounds that exhibit a balance of properties, include potency as well as ADMET [61]. Even though some of our hits exhibited slightly reduced predicted binding free energies relative to the positive control, they exhibited improved predicted pharmacokinetic profiles. Compound **9** (MMGBSA value of \(\sim\!-22\) kcal/mol), which showed a reduced MM-GBSA energy compared with the parent compound, exhibited lower predicted toxicity than parent compound. Many of our hits exhibited comparable predicted binding free energies to that of the most potent co-crystallized ligand. It was previously reported that co-crystallized ligands bound to a highly homologous protein, FimH, have been seen to exhibit two different binding modes: (a) an _in_ docking mode; and (b) an _out_ docking mode [62; 63]. Hits from the [PERSON] et al. and [PERSON] et al. studies exhibited a somewhat _out_ docking mode [14; 18]. Overall, the docking modes of the hits in this study were also bound in the _out_ docking mode. Scaffold hopping is a technique for finding isofunctional but structurally dissimilar chemical matter from libraries of diverse chemotypes that have been rationally designed [64]. In ligand-based scaffold hopping, the binding site of the protein is not taken into account during the screening step, and compounds with novel core motifs are identified that are predicted to have similar biological activities to the template. Ligand-based scaffold hopping is a widely used virtual screening technique in modern drug discovery that is usually faster than receptor-based scaffold hopping [64; 65; 66; 67]. However, it is also crucial to understand how compounds interact with the protein of interest. When information about the binding site is available, receptor-based scaffold hopping allows the identification of novel chemotypes that can interact strongly with the protein [68; 69]. Conceptually, ligand-based screening can generate a higher number of potential hits, while receptor-based screening can help to eliminate false positives. Combining both strategies can help in compound optimization with the aim of improving target binding, ensuring drug-like properties, or reducing toxicity [69; 70]. In this study, we have applied the two screening approaches in parallel to maximize our chances to find hits. A larger number of potential hits having a synthesizability score >0 were obtained from ligand-based screening (1115 from Scaffold 1 hopping and 1109 from Scaffold 2 hopping) compared with receptor-based scaffold hopping (29 from Scaffold 1 hopping and 9 from Scaffold 2 hopping; these structures also satisfied a cut-off criterion of the number of hydrogen bonding interactions with the protein binding pocket). We then used global machine-learning models for pharmacokinetic property prediction, with the aim of obtaining drug-like hits. Leveraging the power of modern-day drug discovery methods, our current study focuses on using in silico approaches to generate a database of matched molecular pairs with a strong predicted binding to FmlH. Scaffold hopping is a valuable approach to generate ideas for the design of novel derivatives and to enhance the intellectual property of drug compounds by developing a synthetically accessible new chemical space. Global machine-learning models to predict the pharmacokinetic properties of the small molecule glycomimetics allow the rapid and accurate prediction of their ADMET profiles and enable multi-parameter optimization (MPO) for hit generation. The potential of FmlH as a drug target and designing galactoside/\(N\)-acetylgalactosamine inhibitors is a relatively new area of research, hence the atomic-level understanding provided in this study can play a crucial role in the development of potent inhibitors with suitable pharmacokinetic profiles.