2026-10-13T05:14:28Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34057653 2026-10-02T18:08:53Z category_1 category_4 category_7 category_12 category_14 category_15 category_19 category_873 category_46 portal_63 item_type_3 month_year_10_2026

Three Distinct Binding Modes Govern High-Affinity Ligand Interactions with Amyloid Fibrils Timothy S. Chisholm (19226586) Biophysics Biochemistry Medicine Cell Biology Molecular Biology Neuroscience Pharmacology Chemical Sciences not elsewhere classified Immunology three distinct high represent attractive biomarkers characteristic fluorescence responses affinity ligand interactions binding ligand scaffolds analyze binding behavior affinity binding modes binding modes interacting binding binding mode binding ligands work outlines therapeutic targets practical framework poor understanding neurodegenerative diseases mathematical framework future fibril findings establish experimental approach defining feature amyloid fibrils Fibrillar protein aggregates are a defining feature of neurodegenerative diseases and represent attractive biomarkers and therapeutic targets. However, the rational design of small-molecule ligands and probes targeting these aggregates is limited by a poor understanding of how ligands bind to amyloid fibrils. This work outlines an experimental approach to determine the binding mode of ligands to amyloid fibrils using previously overlooked information contained within standard binding assays. Using a mathematical framework to analyze binding behavior, three distinct high-affinity binding modes were identified: discrete, overlapping, and interacting binding. Reanalysis of published binding data indicates that these binding modes are widespread among common amyloid-binding ligand scaffolds. Two ligands were designed using principles informed by these binding modes, yielding improved binding affinities and characteristic fluorescence responses. These findings establish a practical framework for determining how small molecules bind amyloid fibrils using straightforward binding assays and for guiding the design of future fibril-binding ligands and probes. 2026-10-02T00:00:00Z Dataset Dataset 10.1021/acs.biochem.6c00489.s002 https://figshare.com/articles/dataset/Three_Distinct_Binding_Modes_Govern_High-Affinity_Ligand_Interactions_with_Amyloid_Fibrils/34057653 CC BY-NC 4.0