Docking to flexible nicotinic acetylcholine receptors: a validation study using the acetylcholine binding protein

Area of Science:

• Structural biology
• Computational chemistry
• Pharmacology

Background:

• The Cys-loop receptor family, including nicotinic acetylcholine receptors (nAChRs), presents computational docking challenges due to C-loop flexibility.
• Acetylcholine binding protein (AChBP) crystal structures reveal ligand-dependent C-loop conformations, making it a valuable model for nAChRs.

Purpose of the Study:

• To develop an unbiased computational docking protocol for nAChRs.
• To investigate the impact of C-loop flexibility on ligand binding.
• To enhance structure-based drug discovery for nAChRs and related receptors.

Main Methods:

• Generated an acetylcholine binding protein (AChBP) ensemble with systematic C-loop closure variations using targeted geometry optimizations.
• Performed computational docking of ligands with known binding modes to the AChBP ensemble.
• Validated the prediction accuracy of ligand binding modes and induced C-loop closure.

Main Results:

• Successfully predicted the binding modes for 12 out of 15 tested ligands.
• Accurately predicted the induced degrees of C-loop closure for 14 out of 15 ligands.
• Demonstrated the efficacy of the ensemble-based docking approach.

Conclusions:

• The developed protocol effectively addresses C-loop flexibility in computational docking to nAChRs.
• This method shows significant potential for advancing structure-based drug discovery targeting nAChRs.
• The approach provides a robust framework for studying ligand-receptor interactions in Cys-loop receptors.