4B5D

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

Summary for 4B5D

• Entry DOI: 10.2210/pdb4b5d/pdb
• Descriptor: 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)
• Functional Keywords: acetylcholine-binding protein, nicotinic receptor, ion channel
• Biological source: CAPITELLA TELETA
• Total number of polymer chains: 5
• Total formula weight: 134908.82

Authors

Nys, M.,Ulens, C. (deposition date: 2012-08-03, release date: 2012-09-26, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.195 Å)