## 1 Introduction
Recent efforts have been made to design and optimize glycomimetic small molecules that can bind strongly to FmIH\({}_{\text{LD}}\) and inhibit the adhesion of UPEC to host cell surfaces and potentially prevent infections [14; 17; 18]. Biphenyl derivatives containing N-acetylgalactosaminosides (GalNAc) showed strong binding to FmIH\({}_{\text{LD}}\) and also exhibited significant inhibitory potency [14; 17; 18]. In a rational drug design study by [PERSON] et al., several GalNAc-containing biphenyl compounds showed activity against FmIH in the nanomolar range. Two of the most potent compounds showed good metabolic stability but poor oral bioavailability [18]. In that work, X-ray co-crystal structures of the potent ligands with FmIH were obtained. The structures can serve as starting points for the design of improved FmIH-binding glycomimetics, using both receptor-based and ligand-based approaches. In our recent work, we designed and implemented a state-of-the-art virtual screening method using a hybrid fragment-based approach [14]. In that work, novel hit glycomimetics that exhibited improved FmIH binding were proposed, along with a database of small molecule aglycone fragments that can be utilized in the identification of FmIH-binding molecules [14]. In this study, we used in silico ligand-based and receptor-based scaffold hopping techniques to obtain novel GalNAc-containing matched molecular pairs (MMPs) that are predicted to exhibit a high binding affinity for FmIH (Figure 1). Scaffold hopping has tremendous potential for generating multiple novel scaffolds that can be screened as part of a search for new lead compounds with improved properties that still preserve key FmIH-ligand interactions. In addition to its role in lead optimization, scaffold hopping is valuable in idea generation on the path to creating new intellectual property. In this study, we considered hits that have high synthesizable accessibility after scaffold hopping. Additional molecular modeling approaches, including molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations, were conducted to further investigate and validate the FmIH-hit binding. We have designed a total of 58 glycomimetics with high synthesizable accessibility scores and have predicted their pharmacokinetic profiles using machine-learning models. Several of the hits exhibited improved predicted ADMET properties relative to the glycomimetic that has been reported as the most potent against FmIH. Our results show promise as a starting point for a novel class of small molecules to serve as potential antivirulence therapies in the treatment of UTIs. The library of molecules provided in this study can serve as an excellent resource for further investigation using in vitro and in vivo studies. Additionally, this study can serve as an attractive area for next-generation research using computer-aided drug design techniques for FmIH-binding glycomimetics discovery. Using the molecular modeling approaches that are adopted in this work can help to expedite the drug design process by reducing the chances of failure of late-stage drug candidates targeting FmIH in the prevention of UTIs.