Flexible docking of ligands into synthetic receptors using a two-sided incremental construction algorithm

Area of Science:

• Computational Chemistry
• Structural Biology
• Molecular Modeling

Background:

• Predicting the structure of synthetic receptor-ligand complexes is crucial for designing novel molecules.
• Existing docking methods may not adequately handle the flexibility of synthetic receptors and ligands.

Purpose of the Study:

• To develop a fast and reliable algorithm for the structure prediction of synthetic receptor-ligand complexes.
• To extend existing docking techniques to accommodate the unique challenges of synthetic molecules.

Main Methods:

• An adaptive two-sided incremental construction algorithm was employed, integrating the flexibility of both ligand and synthetic receptor.
• A novel docking strategy involved iteratively expanding one molecule while treating the other as rigid, then exchanging roles.
• Geometric filters and graph-based precomputation were used to efficiently discard invalid conformations.

Main Results:

• The algorithm achieved near-native structure prediction for 9 out of 10 synthetic receptor-ligand complexes tested.
• The method demonstrated computational efficiency, generating solutions within minutes.
• The algorithm successfully handled the structural flexibility of both interacting molecules.

Conclusions:

• The developed algorithm provides a fast and reliable approach for synthetic receptor-ligand complex structure prediction.
• This method shows significant potential as a virtual screening tool for identifying molecular interactions.
• The approach can be applied to search large databases for suitable guest molecules for synthetic receptors and vice versa.