Surface Plasmon Resonance Biosensor Based Fragment Screening Using Acetylcholine Binding Protein Identifies Ligand Efficiency Hot Spots (LE Hot Spots) by Deconstruction of Nicotinic Acetylcholine Receptor α7 Ligands

G.E. de Kloe, K. Retra, M. Geitmann, B. Kallblad, T.T. Nahar, R. van Elk, A.B. Smit, J.E. van Muijlwijk- Koezen, R. Leurs, H. Irth, U.H. Danielson, I.J.P. de Esch

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The soluble acetylcholine binding protein (AChBP) is a homologue of the ligand-binding domain of the nicotinic acetylcholine receptors (nAChR). To guide future fragment-screening using surface plasmon resonance (SPR) biosensor technology as a label-free, direct binding, biophysical screening assay, a focused fragment library was generated based on deconstruction of a set of α7 nAChR selective quinuclidine containing ligands with nanomolar affinities. The interaction characteristics of the fragments and the parent compounds with AChBP were evaluated using an SPR biosensor assay. The data obtained from this direct binding assay correlated well with data from the reference radioligand displacement assay. Ligand efficiencies for different (structural) groups of fragments in the library were correlated to binding with distinct regions of the binding pocket, thereby identifying ligand efficiency hot spots (LE hot spots). These hot spots can be used to identity the most promising hit fragments in a large scale fragment library screen. © 2010 American Chemical Society.
Original languageEnglish
Pages (from-to)7192-7201
Number of pages9
JournalJournal of Medicinal Chemistry
Volume53
Issue number19
DOIs
Publication statusPublished - 9 Sep 2010

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Surface Plasmon Resonance
Nicotinic Receptors
Biosensing Techniques
Acetylcholine
Carrier Proteins
Ligands
Quinuclidines
Radioligand Assay
Libraries
Technology

Cite this

@article{b8bd94bb0f2e4a78b8dcb51ddc9037fa,
title = "Surface Plasmon Resonance Biosensor Based Fragment Screening Using Acetylcholine Binding Protein Identifies Ligand Efficiency Hot Spots (LE Hot Spots) by Deconstruction of Nicotinic Acetylcholine Receptor α7 Ligands",
abstract = "The soluble acetylcholine binding protein (AChBP) is a homologue of the ligand-binding domain of the nicotinic acetylcholine receptors (nAChR). To guide future fragment-screening using surface plasmon resonance (SPR) biosensor technology as a label-free, direct binding, biophysical screening assay, a focused fragment library was generated based on deconstruction of a set of α7 nAChR selective quinuclidine containing ligands with nanomolar affinities. The interaction characteristics of the fragments and the parent compounds with AChBP were evaluated using an SPR biosensor assay. The data obtained from this direct binding assay correlated well with data from the reference radioligand displacement assay. Ligand efficiencies for different (structural) groups of fragments in the library were correlated to binding with distinct regions of the binding pocket, thereby identifying ligand efficiency hot spots (LE hot spots). These hot spots can be used to identity the most promising hit fragments in a large scale fragment library screen. {\circledC} 2010 American Chemical Society.",
author = "{de Kloe}, G.E. and K. Retra and M. Geitmann and B. Kallblad and T.T. Nahar and {van Elk}, R. and A.B. Smit and {van Muijlwijk- Koezen}, J.E. and R. Leurs and H. Irth and U.H. Danielson and {de Esch}, I.J.P.",
year = "2010",
month = "9",
day = "9",
doi = "10.1021/jm100834y",
language = "English",
volume = "53",
pages = "7192--7201",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "19",

}

Surface Plasmon Resonance Biosensor Based Fragment Screening Using Acetylcholine Binding Protein Identifies Ligand Efficiency Hot Spots (LE Hot Spots) by Deconstruction of Nicotinic Acetylcholine Receptor α7 Ligands. / de Kloe, G.E.; Retra, K.; Geitmann, M.; Kallblad, B.; Nahar, T.T.; van Elk, R.; Smit, A.B.; van Muijlwijk- Koezen, J.E.; Leurs, R.; Irth, H.; Danielson, U.H.; de Esch, I.J.P.

In: Journal of Medicinal Chemistry, Vol. 53, No. 19, 09.09.2010, p. 7192-7201.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Surface Plasmon Resonance Biosensor Based Fragment Screening Using Acetylcholine Binding Protein Identifies Ligand Efficiency Hot Spots (LE Hot Spots) by Deconstruction of Nicotinic Acetylcholine Receptor α7 Ligands

AU - de Kloe, G.E.

AU - Retra, K.

AU - Geitmann, M.

AU - Kallblad, B.

AU - Nahar, T.T.

AU - van Elk, R.

AU - Smit, A.B.

AU - van Muijlwijk- Koezen, J.E.

AU - Leurs, R.

AU - Irth, H.

AU - Danielson, U.H.

AU - de Esch, I.J.P.

PY - 2010/9/9

Y1 - 2010/9/9

N2 - The soluble acetylcholine binding protein (AChBP) is a homologue of the ligand-binding domain of the nicotinic acetylcholine receptors (nAChR). To guide future fragment-screening using surface plasmon resonance (SPR) biosensor technology as a label-free, direct binding, biophysical screening assay, a focused fragment library was generated based on deconstruction of a set of α7 nAChR selective quinuclidine containing ligands with nanomolar affinities. The interaction characteristics of the fragments and the parent compounds with AChBP were evaluated using an SPR biosensor assay. The data obtained from this direct binding assay correlated well with data from the reference radioligand displacement assay. Ligand efficiencies for different (structural) groups of fragments in the library were correlated to binding with distinct regions of the binding pocket, thereby identifying ligand efficiency hot spots (LE hot spots). These hot spots can be used to identity the most promising hit fragments in a large scale fragment library screen. © 2010 American Chemical Society.

AB - The soluble acetylcholine binding protein (AChBP) is a homologue of the ligand-binding domain of the nicotinic acetylcholine receptors (nAChR). To guide future fragment-screening using surface plasmon resonance (SPR) biosensor technology as a label-free, direct binding, biophysical screening assay, a focused fragment library was generated based on deconstruction of a set of α7 nAChR selective quinuclidine containing ligands with nanomolar affinities. The interaction characteristics of the fragments and the parent compounds with AChBP were evaluated using an SPR biosensor assay. The data obtained from this direct binding assay correlated well with data from the reference radioligand displacement assay. Ligand efficiencies for different (structural) groups of fragments in the library were correlated to binding with distinct regions of the binding pocket, thereby identifying ligand efficiency hot spots (LE hot spots). These hot spots can be used to identity the most promising hit fragments in a large scale fragment library screen. © 2010 American Chemical Society.

U2 - 10.1021/jm100834y

DO - 10.1021/jm100834y

M3 - Article

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EP - 7201

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -