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

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,...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-10, Vol.53 (19), p.7192-7201
Main Authors: de Kloe, Gerdien E, Retra, Kim, Geitmann, Matthis, Källblad, Per, Nahar, Tariq, van Elk, René, Smit, August B, van Muijlwijk-Koezen, Jacqueline E, Leurs, Rob, Irth, Hubertus, Danielson, U. Helena, de Esch, Iwan J. P
Format: Article
Language:English
Subjects:
Animals
Aplysia
Binding Sites
Binding, Competitive
Biosensing Techniques
Carbamates - chemical synthesis
Carbamates - chemistry
Carrier Proteins - chemistry
FARMACI
Humans
Ligands
Lymnaea
MEDICIN
MEDICINE
Models, Molecular
NATURAL SCIENCES
NATURVETENSKAP
PHARMACY
Pyridines - chemical synthesis
Pyridines - chemistry
Quinuclidines - chemical synthesis
Quinuclidines - chemistry
Radioligand Assay
Receptors, Nicotinic - chemistry
Structure-Activity Relationship
Surface Plasmon Resonance
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Summary: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.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/jm100834y