Deciphering the Distinctive Features of Alpha‐D‐mannopyranoside Structure From Similar Structures Against FimH Through ANN and PCA: Insights and Perspectives

This computational study aimed to demonstrate distinct characteristics of alpha‐D‐mannopyranoside structure, leveraging D‐mannose and its analogs due to their known roles in host–pathogen interactions and potential to be used as nutraceuticals. Targeting bacterial adhesion is a critical strategy to combat urinary tract infections (UTIs), especially given rising antibiotic resistance. The FimH lectin on Escherichia coli is a key mediator of this adhesion, making it a compelling target for novel anti‐adhesive therapies. We employed a multi‐stage virtual screening pipeline to efficiently explore a vast chemical space around the ligands and their binding interactions. Ligand‐based virtual screening, utilizing self‐organizing maps (SOMs), clustered 5256 D‐mannose‐similar structures, identifying a promising subset of 141 molecules with 39 known bioassay actives. This was followed by structure‐based ligand docking to precisely evaluate their inhibitory impact on FimH lectin. To understand the structural features driving activity, principal component analysis (PCA) was then applied to analyze the molecular structures and their physicochemical descriptors. Our analysis revealed that 15 compounds exhibited the highest binding energy and docking scores. Crucially, the alpha‐D‐mannopyranoside conformation demonstrated the most effective inhibitory profile. This superior activity, despite structural similarities, was differentiated by two 3D‐matrix descriptors: HRG and Wi G, highlighting their significance in predicting subtle yet impactful conformational preferences.