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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis

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Ensemble Docking for Intrinsically Disordered Proteins.

Anjali Dhar1, Thomas R Sisk1, Paul Robustelli1

  • 1Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, United States.

Journal of Chemical Information and Modeling
|June 18, 2025
PubMed
Summary
This summary is machine-generated.

New ensemble docking methods accurately predict small molecule binding to intrinsically disordered proteins (IDPs), aiding drug discovery for diseases linked to these challenging targets.

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Area of Science:

  • Biochemistry
  • Computational Biology
  • Drug Discovery

Background:

  • Intrinsically disordered proteins (IDPs) are crucial in human diseases but difficult to target with conventional drug design.
  • Traditional structure-based methods fail due to the lack of fixed binding sites in IDPs.

Purpose of the Study:

  • To develop and validate computationally efficient ensemble docking approaches for IDPs.
  • To characterize the dynamic binding mechanisms of small molecules to IDPs at atomic resolution.

Main Methods:

  • Ensemble docking protocols were employed to predict relative binding affinities of small molecules to IDPs.
  • Methods were validated against NMR spectroscopy data for α-synuclein ligands.
  • Generated binding mode ensembles were compared with long-time scale molecular dynamics simulations.

Main Results:

  • Ensemble docking accurately predicted the relative binding affinities of three α-synuclein ligands.
  • Predicted ligand binding modes showed excellent agreement with molecular dynamics simulations.
  • The study characterized the dynamic and heterogeneous nature of small molecule binding to IDPs.

Conclusions:

  • Ensemble docking is a promising computational tool for predicting small molecule binding to IDPs.
  • These methods can accelerate drug discovery campaigns targeting IDPs.
  • The approach offers insights into the atomic-level binding mechanisms of IDPs.