Discovery of Novel alpha 4 beta 2 Neuronal Nicotinic Receptor Modulators through Structure-Based Virtual Screening

作者：Mahasenan Kiran V; Pavlovicz Ryan E; Henderson Brandon J; Gonzalez Cestari Tatiana F; Yi Bitna; McKay Dennis B; Li Chenglong^*

来源：ACS Medicinal Chemistry Letters, 2011, 2(11): 855-860.

DOI：10.1021/ml2001714

• nAChR
• nicotinic acetylcholine receptor
• virtual screening
• allosteric
• noncompetitive antagonists
• AChBP

We performed a hierarchical structure-based virtual screening utilizing a comparative model of the human alpha 4 beta 2 neuronal nicotinic acetylcholine receptor (nAChR) extracellular domain. Compounds were selected for experimental testing based on structural diversity, binding pocket location, and standard error of the free energy scoring function used in the screening. Four of the eleven in silico hit compounds showed promising activity with low micromolar IC50 values in a calcium accumulation assay. Two of the antagonists were also proven to be selective for human alpha 4 beta 2 vs human alpha 3 beta 4 nAChRs. This is the first report of successful discovery of novel nAChR antagonists through the use of structure-based virtual screening with a human nAChR homology model. These compounds may serve as potential novel scaffolds for further development of selective nAChR antagonists.

• 出版日期2011-11