Department
neurobiology
Document Type
Article
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. © 2012 American Chemical Society.
Publication Date
9-27-2012
Publication Title
Journal of Medicinal Chemistry
ISSN
00222623
Volume
55
Issue
18
First Page
8028
Last Page
8037
Digital Object Identifier (DOI)
10.1021/jm3008739
Recommended Citation
Zhang, Han Kun; Eaton, J. Brek; Yu, Li Fang; Nys, Mieke; Mazzolari, Angelica; Elk, Rene Van; Smit, August B.; Alexandrov, Vadim; Hanania, Taleen; Sabath, Emily; Fedolak, Allison; Brunner, Daniela; Lukas, Ronald J.; Vistoli, Giulio; Ulens, Chris; and Kozikowski, Alan P., "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" (2012). Translational Neuroscience. 234.
https://scholar.barrowneuro.org/neurobiology/234