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, 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.
de Kloe
Gerdien E
GE
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.
Retra
Kim
K
Geitmann
Matthis
M
Källblad
Per
P
Nahar
Tariq
T
van Elk
René
R
Smit
August B
AB
van Muijlwijk-Koezen
Jacqueline E
JE
Leurs
Rob
R
Irth
Hubertus
H
Danielson
U Helena
UH
de Esch
Iwan J P
IJ
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
C428944:AChBP protein, Lymnaea; D002219:Carbamates; D002352:Carrier Proteins; D008024:Ligands; D011725:Pyridines; D011812:Quinuclidines; D011978:Receptors, Nicotinic; C104518:nicotinic receptor alpha6