Identification of novel ?7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric ?7 receptor ligand binding domain.

ABSTRACT: A hierarchical in silico screening procedure using the crystal structure of an agonist bound chimeric ?7/Ls-AChBP protein was successfully applied to both proprietary and commercial databases containing drug-like molecules. An overall hit rate of 26% (pK(i) ?5.0) was obtained, with an even better hit rate of 35% for the commercial compound collection. Structurally novel and diverse ligands were identified. Binding studies with [(3)H]epibatidine on chimeric ?7/5-HT(3) receptors yielded submicromolar inhibition constants for identified hits. Compared to a previous screening procedure that utilized the wild type Ls-AChBP crystal structure, the current study shows that the recently obtained ?7/Ls-AChBP chimeric protein crystal structure is a better template for the identification of novel ?7 receptor ligands.

SUBMITTER: Akdemir A 

PROVIDER: S-EPMC3460237 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature