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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
Published on: June 20, 2025
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Water-guided docking improves prediction of protein-glycan complexes
J O Lannot1,2, E L Rey1,2, M D Gamarra1,2
1Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (FCEyN-UBA), Pabellón 2 de Ciudad Universitaria, Ciudad de Buenos Aires C1428EHA, Buenos Aires, Argentina.
Glycobiology
|January 16, 2026
Summary
We developed a guided docking protocol using crystallographic water sites (CWS) to improve protein-carbohydrate complex structure prediction. This novel approach enhances glycan pose prediction accuracy for drug discovery.
Area of Science:
- Structural biology
- Computational chemistry
- Glycosciences
Background:
- Predicting protein-carbohydrate complex structures is difficult due to glycan flexibility and binding site characteristics.
- Accurate modeling is crucial for understanding biological processes and designing therapeutics.
Purpose of the Study:
- To develop and validate a novel guided docking protocol for enhanced glycan pose prediction.
- To leverage crystallographic water sites (CWS) for improved accuracy in modeling protein-glycan interactions.
Main Methods:
- Developed the WII Guided Approach (WIIGA) using AutoDock Vina (ADV) and crystallographic water sites (CWS).
- Defined Waters Ideal Interactions (WII) from apo structures to guide docking simulations.
- Benchmarked WIIGA against conventional methods using a dataset of 30 protein-oligosaccharide complexes.
Main Results:
- The WIIGA protocol significantly outperformed existing methods (ADV, VC, VC CH-π, GTV) in pose prediction accuracy.
- Achieved robust performance even without holo structures and successfully cross-docked glycomimetics.
- Demonstrated improved accuracy across a range of oligosaccharide lengths (tetra- to nonasaccharides).
Conclusions:
- Solvent-derived information, specifically CWS, is valuable for enhancing molecular docking accuracy.
- The WIIGA protocol offers a versatile and easily implementable tool for glyco-ligand modeling and structure-based design.
- This approach advances the field of structural glycobiology and aids in the development of glycan-binding protein therapeutics.
