Template-guided method for protein-ligand complex structure prediction: Application to CASP15 protein-ligand studies

Area of Science:

• Computational biology
• Structural biology
• Drug discovery

Background:

• Protein-ligand modeling is crucial for drug discovery.
• The Critical Assessment of Structure Prediction 15 (CASP15) introduced ligand prediction to spur method development.

Purpose of the Study:

• To evaluate a novel template-guided method for protein-ligand complex structure prediction.
• To assess the method's performance in the CASP15 ligand prediction category.

Main Methods:

• A template-guided approach combining physicochemical molecular docking and bioinformatics-based ligand similarity.
• Utilizing homologous or similar-fold protein structures from the Protein Data Bank as templates.
• Employing co-bound ligand binding modes from templates to guide target complex structure prediction.

Main Results:

• The method ranked second overall in the CASP15 protein-ligand prediction category when considering the top predicted model.
• The approach demonstrated effectiveness in guiding complex structure prediction using template information.

Conclusions:

• The template-guided method shows strong performance in protein-ligand complex structure prediction.
• Challenges remain, including handling protein conformational changes, large/flexible ligands, and multiple ligands in binding pockets.