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

Computational docking to nicotinic acetylcholine receptors (nAChRs) and other members of the Cys-loop receptor family is complicated by the flexibility of the so-called C-loop. As observed in the large number of published crystal structures of the acetylcholine binding protein (AChBP), a structural surrogate and homology modeling template for the nAChRs, the conformation of this loop is controlled by the ligand present in the binding pocket. As part of the development of a protocol for unbiased docking to the nAChRs, we here present the results of docking of ligands with known binding modes to an AChBP ensemble with systematic variations in C-loop closure generated via a series of targeted geometry optimizations. We demonstrate the ability to correctly predict binding modes for 12 out of 15 ligands and induced degrees of C-loop closure for 14 out of 15 ligands. Our approach holds a promising potential for structure based drug discovery within nAChRs and related receptors.

Graphical abstract.Figure optionsDownload full-size imageDownload high-quality image (120 K)Download as PowerPoint slideResearch highlights▶ Docking to flexible acetylcholine binding proteins ▶ Ensemble generation through targeted molecular mechanics optimization ▶ Ensemble docking ▶ 83% of experimentally validated binding modes and C-loop closures determined correctly.