Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain
Research output: Contribution to journal › Journal article › Research › peer-review
Atilla Akdemir, Ewald Edink, Andrew J. Thompson, Sarah C.R. Lummis, Albert J. Kooistra, Chris De Graaf, Iwan J.P. De Esch
A hierarchical in silico screening procedure using the crystal structure of an agonist bound chimeric α7/Ls-AChBP protein was successfully applied to both proprietary and commercial databases containing drug-like molecules. An overall hit rate of 26% (pKi ≥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 [ 3H]epibatidine on chimeric α7/5-HT3 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 α7/Ls-AChBP chimeric protein crystal structure is a better template for the identification of novel α7 receptor ligands.
|Journal||Bioorganic and Medicinal Chemistry|
|Number of pages||11|
|Publication status||Published - 1 Oct 2012|
- α7 Receptor, AChBP, Cys-loop, Docking, In silico screening, nAChR, Virtual screening