Insights into the structural determinants required for high-affinity binding of chiral cyclopropane-containing ligands to ?4?2-nicotinic acetylcholine receptors: an integrated approach to behaviorally active nicotinic ligands.

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 ?4?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 ?4?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 ?4?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.

SUBMITTER: Zhang HK 

PROVIDER: S-EPMC3464052 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature