摘要

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 alpha 7 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 alpha 7 receptor antagonists and as non-competitive alpha 4 beta 2 receptor inhibitors. These results underline the usability of AChBP in structure-based in silico screening strategies in finding novel scaffolds for the alpha 7 receptor, but also illustrates some limitations of using AChBP as bait to find competitive alpha 4 beta 2 receptor ligands and alpha 7 receptor agonists.

  • 出版日期2011-10-15