Finding ligands to selectively bind to nicotinic acetylcholine receptor family of ligand gated ion channels is challenging due to the diversity of receptor subtypes, but ligands for the α7 subtype in particular could lead to new therapies for brain disorders such as schizophrenia and Alzheimer’s disease.
To screen for potential ligands Jeroen Kool (Leiden/Amsterdam Center for Drug Research) and colleagues recently developed an online fluorescence enhancement assay for the water-soluble acetylcholine binding protein (AChBP) – a model protein for the binding domain of α7 nicotinic acetylcholine receptors. Using the related proteins Ls and Ac-AChBP they sifted through in-house fragment libraries, discovering that Ls-AChBP is a better template for fragment screening and accurate, rapid hit exploration is possible using single point injections in the 96-well format. They also produced an optimised hit with mM affinity for the α7 nicotinic acetylcholine receptor.
The authors hope that this technology will find applicability elsewhere – as it only requires a water-soluble protein and a good fluorescence enhancement tracer ligand.
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Online parallel fragment screening and rapid hit exploration for nicotinic acetylcholine receptors
Gerdien E. de Kloe, Jeroen Kool, Rene van Elk, Jacqueline E. van Muijlwijk-Koezen, August B. Smit, Henk Lingeman, Hubertus Irth, Wilfried M. A. Niessen and Iwan J. P. de Esch
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00031D
