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Discovery of Novel ?4?2 Neuronal Nicotinic Receptor Modulators through Structure-Based Virtual Screening.

ABSTRACT: We performed a hierarchical structure-based virtual screening utilizing a comparative model of the human ?4?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 ?4?2 vs human ?3?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.

SUBMITTER: Mahasenan KV

PROVIDER: S-EPMC4056858 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Discovery of Novel α4β2 Neuronal Nicotinic Receptor Modulators through Structure-Based Virtual Screening.

Mahasenan Kiran V KV Pavlovicz Ryan E RE Henderson Brandon J BJ González-Cestari Tatiana F TF Yi Bitna B McKay Dennis B DB Li Chenglong C

ACS medicinal chemistry letters 20110918 11

We performed a hierarchical structure-based virtual screening utilizing a comparative model of the human α4β2 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. T ...[more]

PMID: 24936233

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