4b5d

Publication Abstract from PubMed

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 alpha4beta2-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 alpha4beta2-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 alpha4beta2-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.

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.,Zhang HK, Eaton JB, Yu LF, Nys M, Mazzolari A, van Elk R, Smit AB, Alexandrov V, Hanania T, Sabath E, Fedolak A, Brunner D, Lukas RJ, Vistoli G, Ulens C, Kozikowski AP J Med Chem. 2012 Sep 7. PMID:22928944^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.