CNS Drugs Target Functional Bacterial Amyloids: A FuBA Pocketography and Engagement Index Study

Abstract- Emerging evidence suggests that bacterial functional amyloids (FuBA) in the gut may influenceneurodegenerative disease pathways. Here, we computationally evaluated approved and investigational CNS ligandsassociated with Alzheimer’s disease (AD) and Parkinson’s disease (PD) for their potential to engage two model bacterialamyloids, RepA-WH1 (1HKQ) and TasA (5OF1). Drug-receptor interactions derived from curated docking outputs andresidue-level analyses revealed a conserved LEU211-anchored pocket on TasA accessed by both AD and PD ligands, butwith disease-class-specific micro-subpocket preferences. AD-associated molecules frequently favored a LEU211–GLY210–ASN215–LYS216 quadrant, whereas several PD agents exhibited enhanced interactions across LEU211–ASP207–VAL213–LYS209. Concurrently, RepA consistently displayed a PRO39–LEU40–ILE34–THR120 hydrophobicgroove motif enriched for ligands bearing multi-ring scaffolds and cationic centers, supporting a minimal pharmacophore“WH1-groove rule.” Cross-protein concordance for select molecules (e.g., Idalopirdine, Methixene, Donepezil) suggesteddual FuBA engagement potential, motivating experimental prioritization. To formalize this signal, we propose a FuBAEngagement Index (FEI) based on recurrence of hotspot residues, enabling rapid ligand triaging across amyloid targets.This integrative pocketography approach indicates that clinically validated CNS chemotypes may harbor latent capacitiesto interact with microbial amyloid interfaces, offering an unreported mechanistic bridge between drug structure,bacterial amyloid modulation, and gut–brain axis hypotheses. These findings provide a reproducible computationalfoundation and a ranked ligand shortlist to stimulate follow-up molecular dynamics and biofilm/aggregation assays forfunctional validation.