Insights into the Structural Determinants Required for High-Affinity Binding of Chiral Cyclopropane-Containing Ligands to 伪4尾2-Nicotinic Acetylcholine Receptors: An Integrated Approach to Behaviorally

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• 作者：Han-Kun Zhang ; J. Brek Eaton ; Li-Fang Yu ; Mieke Nys ; Angelica Mazzolari ; Ren茅 van Elk ; August B. Smit ; Vadim Alexandrov ; Taleen Hanania ; Emily Sabath ; Allison Fedolak ; Daniela Brunner ; Ronald J. Lukas ; Giulio Vistoli ; Chris Ulens ; Alan P. Kozikowski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 27, 2012
• 年：2012
• 卷：55
• 期：18
• 页码：8028-8037
• 全文大小：507K
• 年卷期：v.55,no.18(September 27, 2012)
• ISSN：1520-4804

文摘

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 伪4尾2-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 伪4尾2-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 伪4尾2-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.