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oai:figshare.com:article/34025323 2026-09-29T17:12:20Z category_1 category_4 category_915 category_7 category_13 category_14 category_19 category_873 category_46 category_734 category_64 portal_63 item_type_6 month_year_09_2026

Binding without Docking: Small-Molecule Binding Paths on Disordered Proteins Adelie Louet (25138126) Gerhard Hummer (90147) Michele Vendruscolo (68357) Biophysics Biochemistry Physical Sciences not elsewhere classified Medicine Genetics Molecular Biology Pharmacology Chemical Sciences not elsewhere classified Immunology Biological Sciences not elsewhere classified Cancer transition probabilities capture transient residue clusters time scales comparable residues simultaneously contacting overall residence time identifying druggable regions dissociation constants consistent transient binding sites static binding pockets defined binding pockets conventional binding pockets binding without docking markov state model molecule binding paths dynamic binding paths small molecules interact binding paths molecule binding binding path state corresponds small molecules dynamic mapping stochastic sequence readily characterized parkinson ’ msm enables msm ), lack well experimental measurements drug design disordered proteins disordered protein diffuses across cluster forming characterizing small challenging targets approach using approach provides alzheimer ’ Disordered proteins are challenging targets for drug design because they lack well-defined binding pockets. Small molecules can bind them, but when the bound state remains conformationally heterogeneous, these interactions are not readily characterized in terms of conventional binding pockets. Here, we use the concept of binding paths to describe how small molecules interact with disordered proteins. A binding path is a stochastic sequence of transient residue clusters that a ligand engages as it diffuses across a disordered protein, with each cluster forming and breaking up on time scales comparable to the overall residence time. We formalize this approach using a Markov state model (MSM), in which each state corresponds to a set of residues simultaneously contacting the ligand and the transition probabilities capture how the ligand moves between these sets. We apply this framework to the interactions of 10074-G5 with Aβ42 and of fasudil with α-synuclein, two disordered proteins associated with Alzheimer’s disease and Parkinson’s disease, respectively. The MSM enables both a dynamic mapping of transient binding sites and a calculation of dissociation constants consistent with experimental measurements. By generalizing the concept of static binding pockets to dynamic binding paths, this approach provides a quantitative framework for characterizing small-molecule binding by disordered proteins and for identifying druggable regions on these challenging targets. 2026-09-29T00:00:00Z Text Journal contribution 10.1021/jacs.6c05891.s001 https://figshare.com/articles/journal_contribution/Binding_without_Docking_Small-Molecule_Binding_Paths_on_Disordered_Proteins/34025323 CC BY-NC 4.0