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Updated: Jul 28, 2025
08:49
Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
Published on: June 20, 2025
394
Worth the weight: Sub-Pocket EXplorer (SubPEx), a weighted-ensemble method to enhance binding-pocket conformational
Erich Hellemann1, Jacob D Durrant1
1Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, 15260, United States.
Biorxiv : the Preprint Server for Biology
|May 30, 2023
Summary
Structure-based virtual screening (VS) identifies drug candidates but misses alternate binding sites. Sub-Pocket EXplorer (SubPEx) uses weighted ensemble path sampling to explore pocket flexibility, improving ligand discovery.
Area of Science:
- Computational chemistry
- Drug discovery
- Structural biology
Background:
- Traditional structure-based virtual screening (VS) often fails to identify ligands binding to alternative protein conformations.
- Exploring protein binding-pocket flexibility is crucial for comprehensive ligand discovery.
Approach:
- Introduced Sub-Pocket EXplorer (SubPEx), a novel approach utilizing weighted ensemble (WE) path sampling.
- SubPEx accelerates the exploration of binding-pocket conformational landscapes.
Key Points:
- Successfully applied SubPEx to heat shock protein 90, influenza neuraminidase, and yeast hexokinase 2.
- Demonstrated the ability of SubPEx to identify ligands for diverse protein targets.
Conclusions:
- SubPEx enhances virtual screening by effectively sampling protein pocket flexibility.
- This method improves the identification of potential small-molecule ligands for drug discovery.
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