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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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Date
2012-10-01
Authors
THOMPSON, AJ
de, Graaf
Akdemir, ATİLLA
de, Esch
KOOISTRA, AJ
EDINK, E
LUMMIS, SC
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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.
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α7
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Akdemir A., EDINK E., THOMPSON A., LUMMIS S., KOOISTRA A., de G., de E., -Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain.-, Bioorganic & medicinal chemistry, cilt.20, ss.5992-6002, 2012
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