4B5D

Capitella teleta AChBP in complex with psychonicline (3-((2(S)- Azetidinyl)methoxy)-5-((1S,2R)-2-(2-hydroxyethyl)cyclopropyl)pyridine)

4B5D の概要

• エントリーDOI: 10.2210/pdb4b5d/pdb
• 分子名称: CAPITELLA TELETA ACHBP, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-[(1R,2S)-2-[5-[[(2S)-azetidin-2-yl]methoxy]pyridin-3-yl]cyclopropyl]ethanol, ... (5 entities in total)
• 機能のキーワード: acetylcholine-binding protein, nicotinic receptor, ion channel
• 由来する生物種: CAPITELLA TELETA
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 134908.82

構造登録者

Nys, M.,Ulens, C. (登録日: 2012-08-03, 公開日: 2012-09-26, 最終更新日: 2024-11-06)

主引用文献

Zhang, H.,Eaton, J.B.,Yu, L.,Nys, M.,Mazzolari, A.,Van Elk, R.,Smit, A.B.,Alexandrov, V.,Hanania, T.,Sabath, E.,Fedolak, A.,Brunner, D.,Lukas, R.J.,Vistoli, G.,Ulens, C.,Kozikowski, A.P.
Insights Into the Structural Determinants Required for High- Affinity Binding of Chiral Cyclopropane-Containing Ligands to Alpha4Beta2-Nicotinic Acetylcholine Receptors: An Integrated Approach to Behaviorally Active Nicotinic Ligands.
J.Med.Chem., 55:8028-, 2012

PubMed 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.

PubMed: 22928944
DOI: 10.1021/JM3008739

実験手法

X-RAY DIFFRACTION (2.195 Å)