Binding without Docking: Small-Molecule Binding Paths on Disordered Proteins.
- 1Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, 60438Germany.
- 2Institute of Biophysics, Goethe University Frankfurt, Frankfurt am Main60438, Germany.
- 3Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
Abstract
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.
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BibTeX
@article{louet2026binding,
title = {{Binding without Docking: Small-Molecule Binding Paths on Disordered Proteins.}},
author = {Adelie Louet and Gerhard Hummer and Michele Vendruscolo},
journal = {Journal of the American Chemical Society},
year = {2026},
month = oct,
doi = {10.1021/jacs.6c05891},
url = {https://europepmc.org/article/MED/42913553},
note = {CC BY},
}
RIS
TY - JOUR
TI - Binding without Docking: Small-Molecule Binding Paths on Disordered Proteins.
AU - Adelie Louet
AU - Gerhard Hummer
AU - Michele Vendruscolo
PY - 2026
DA - 2026/10/01
JO - Journal of the American Chemical Society
DO - 10.1021/jacs.6c05891
UR - https://europepmc.org/article/MED/42913553
AB - 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.
SN - 0002-7863
SN - 1520-5126
ER -