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Bioorg Med Chem. 2012 Oct 1;20(19):5992-6002. doi: 10.1016/j.bmc.2012.06.054. Epub 2012 Jul 11.

Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain.

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  • 1Division of Pharmacology, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul, Turkey.

Abstract

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% (pK(i) ≥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 [(3)H]epibatidine on chimeric α7/5-HT(3) 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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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