Structure-Guided Docking of Benzene-1,3-disulfonic Acid to the ApoE-HSPG Binding Site at Arginine 146 as a Christchurch-Mimetic Therapeutic Strategy for Alzheimer’s Disease

Background: The APOΕ3 Christchurch (APOΕ3Ch) variant, characterized by an R136S substitution, confers protection against Alzheimer’s disease (AD) by reducing Apolipoprotein E (ApoE) binding to heparan sulfate proteoglycans (HSPGs), thereby limiting tau propagation. While antibody-based strategies mimicking this variant have shown promise, small-molecule approaches to disrupt the ApoE–HSPG interaction remain underexplored. Methods: We conducted a structure-guided molecular docking study targeting the ApoE HSPG-binding domain centered on Arg146, using AutoDock Vina within the SAMSON platform. The ligand benzene-1,3-disulfonic acid, a small, anionic molecule with structural similarity to sulfated glycosaminoglycans, was docked to the cationic surface of ApoΕ3. Binding affinity, interaction pose, and root-mean-square deviation (RMSD) were assessed. Pharmacokinetic and toxicity predictions were performed using the pkCSM web server. Results: Benzene-1,3-disulfonic acid exhibited strong binding to the Arg146-containing pocket with a top docking score of –5.93 kcal/mol and an estimated inhibition constant (Ki) of 44.6 µmol. The top-ranked pose revealed stabilizing electrostatic interactions and hydrogen bonds with Arg146 and neighboring basic residues. pkCSM profiling predicted poor oral absorption and limited blood-brain barrier permeability, but a favorable safety profile, including no predicted hepatotoxicity, hERG inhibition (cardiac toxicity), or mutagenicity. Conclusion: These findings establish the feasibility of targeting the ApoE–HSPG interface with small molecules and identify benzene-1,3-disulfonic acid as a candidate Christchurch mimetic. While pharmacokinetic limitations preclude systemic use, intranasal delivery or ligand optimization may overcome brain access barriers. This study provides a foundation for developing novel small-molecule therapeutics to disrupt ApoE-mediated tau pathology in AD.