National Center for
2XNT: Acetylcholine Binding Protein (Achbp) As Template For Hierarchical In Silico Screening Procedures To Identify Structurally Novel Ligands For The Nicotinic Receptors
Acetylcholine binding protein (AChBP) as template for hierarchical in silico screening procedures to identify structurally novel ligands for the nicotinic receptors
Bioorg. Med. Chem. (2011) 19 p.6107-6119
Hierarchical in silico screening protocols against the agonist bound acetylcholine binding protein (AChBP) crystal structure were efficient in identifying novel chemotypes for AChBP and the human alpha7 receptor. Two hit structures were cocrystallized with AChBP revealing intermolecular cation-pi interactions with loop C but lacking intermolecular hydrogen bonding. The compounds act as competitive alpha7 receptor antagonists and as non-competitive alpha4beta2 receptor inhibitors. These results underline the usability of AChBP in structure-based in silico screening strategies in finding novel scaffolds for the alpha7 receptor, but also illustrates some limitations of using AChBP as bait to find competitive alpha4beta2 receptor ligands and alpha7 receptor agonists.