HOT article: fragment screening for nicotinic acetylcholine receptors

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.

Why not download the article and see for yourself – it’s currently free to access:

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

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4 Responses to “HOT article: fragment screening for nicotinic acetylcholine receptors”

  1. Kevin says:

    Hi, Thanks for the article. I click to download, but it take me to another site but not download link? Please help.

    (Report comment)

  2. Lorena Tomas Laudo says:

    Hi Kevin,
    The link will take you to the landing page of the article and you will have the PDF link to download it. You may have to sing up for a free personal account http://pubs.rsc.org/en/account/register
    Please let me know if you have any problems.
    Thanks and enjoy the article!

    (Report comment)

  3. Jeroen Kool says:

    We reported the development of an online fluorescent enhancement assay for fragment screening, which is broadly applicable, since it only requires a water-soluble protein and a good fluorescence enhancement tracer ligand. The online bioaffinity assay is sensitive enough for fragment screening and ranking.
    In addition, the assay is suitable for rapid hit exploration. The first steps in fragment growing, from (low) millimolar affinities to optimized fragments with micromolar affinities, are generally regarded as challenging. The small fragments often have only a few interaction points. In docking experiments, multiple equally-scored binding modes are obtained. Even crystal structures are difficult to interpret, because the fragment is likely to fit in different ways in the electron density. It is therefore attractive to explore chemical space around a fragment hit in a rapid manner. The resulting low micromolar ligands are likely to have more interaction points with the protein, which makes the prediction of docking modes easier. These ligands can be subsequently optimized using structure-based design.

    (Report comment)

  4. Paul says:

    I am looking for a source to obtain AChBP for research that I am doing. I am developing a new mass spectrometry based way to determine ligand binding studies and would like to get a relatively inexpensive source for AChBP.

    Thanks in advance.

    (Report comment)

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