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Title: Insights into the Structural Determinants Required for High-Affinity Binding of Chiral Cyclopropane-Containing Ligands to α4β2-Nicotinic Acetylcholine Receptors: An Integrated Approach to Behaviorally Active Nicotinic Ligands
Authors: Zhang, Han-Kun ×
Eaton, J Brek
Yu, Li-Fang
Nys, Mieke
Mazzolari, Angelica
van Elk, René
Smit, August B
Alexandrov, Vadim
Hanania, Taleen
Sabath, Emily
Fedolak, Allison
Brunner, Daniela
Lukas, Ronald J
Vistoli, Giulio
Ulens, Chris
Kozikowski, Alan P #
Issue Date: Sep-2012
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:55 issue:18 pages:8028-8037
Abstract: Structure-based drug design can potentially accelerate the development of new therapeutics. In this study, a cocrystal structure of the acetylcholine binding protein (AChBP) from Capitella teleta (Ct) in complex with a cyclopropane-containing selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonist (compound 5) was acquired. The structural determinants required for ligand binding obtained from this AChBP X-ray structure were used to refine a previous model of the human α4β2-nAChR, thus possibly providing a better understanding of the structure of the human receptor. To validate the potential application of the structure of the Ct-AChBP in the engineering of new α4β2-nAChR ligands, homology modeling methods, combined with in silico ADME calculations, were used to design analogues of compound 5. The most promising compound, 12, exhibited an improved metabolic stability in comparison to the parent compound 5 while retaining favorable pharmacological parameters together with appropriate behavioral end points in the rodent studies.
URI: 
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Structural Neurobiology
× corresponding author
# (joint) last author

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