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, Gerdien E (author)

Retra, Kim (author)

Geitmann, Matthis (author)

Källblad, Per (author)

Nahar, Tariq (author)

van Elk, René (author)

Smit, August B (author)

van Muijlwijk-Koezen, Jacqueline E (author)

Leurs, Rob (author)

Irth, Hubertus (author)

Danielson, U. Helena, 1959- (author): Uppsala universitet,Biokemi,U Helena Danielson

de Esch, Iwan J P (author)

(creator_code:org_t)

2010-09-09
2010
English.
In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:19, s. 7192-7201

Related links:: https://urn.kb.se/re...; show more...; https://doi.org/10.1...; show less...

Abstract Subject headings

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.

By the author/editor: de Kloe, Gerdien ...; Retra, Kim; Geitmann, Matthi ...; Källblad, Per; Nahar, Tariq; van Elk, René; show more...; Smit, August B; van Muijlwijk-Ko ...; Leurs, Rob; Irth, Hubertus; Danielson, U. He ...; de Esch, Iwan J ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Pharmaceutical S ...

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