Design of novel α7-subtype-preferring nicotinic acetylcholine receptor agonists: Application of docking and MM-PBSA computational approaches, synthetic and pharmacological studies

In the search for nicotinic acetylcholine receptor (nAChRs) agonists with a selective affinity for the homomeric α7 channels, we carried out the virtual screening of a test set of potential nicotinic ligands, and adopted a simplified MM-PBSA approach to estimate their relative binding free energy values. By means of this procedure, previously validated by a training set of compounds, we reached a realistic compromise between computational accuracy and calculation rate, and singled out a small group of novel structurally related derivatives characterized by a promising theoretical affinity for the α7 subtype. Among them, five new compounds were synthesized and assayed in binding experiments at neuronal α7 as well as α4β2 nAChRs.

Graphical abstractWe docked about 150 compounds in a model of the α7 neuronal nicotinic receptor, and applied a validated, simplified MM-PBSA approach to estimate their relative binding free energy values. Five structural analogues were selected, synthesized, and tested for binding affinity at α7 and α4β2 subtypes.Figure optionsDownload full-size imageDownload as PowerPoint slide