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.
authors.affiliation: Leiden/Amsterdam Center for Drug Research (LACDR), Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Gerdien E
authors.initials: GE
authors.lastname: de Kloe
authors.forename: Kim
authors.initials: K
authors.lastname: Retra
authors.forename: Matthis
authors.initials: M
authors.lastname: Geitmann
authors.forename: Per
authors.initials: P
authors.lastname: Källblad
authors.forename: Tariq
authors.initials: T
authors.lastname: Nahar
authors.forename: René
authors.initials: R
authors.lastname: van Elk
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: van Muijlwijk-Koezen
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Hubertus
authors.initials: H
authors.lastname: Irth
authors.forename: U Helena
authors.initials: UH
authors.lastname: Danielson
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
mesh_terms: D000818:Animals; D001048:Aplysia; D001665:Binding Sites; D001667:Binding, Competitive; D015374:Biosensing Techniques; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry*; D002352:Carrier Proteins / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008195:Lymnaea; D008958:Models, Molecular; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry*; D011812:Quinuclidines / Q000138:chemical synthesis / Q000737:chemistry*; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000737:chemistry*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: C428944:AChBP protein, Lymnaea; D002219:Carbamates; D002352:Carrier Proteins; D008024:Ligands; D011725:Pyridines; D011812:Quinuclidines; D011978:Receptors, Nicotinic; C104518:nicotinic receptor alpha6