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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
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 hi...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460237/ https://www.ncbi.nlm.nih.gov/pubmed/22959526 http://dx.doi.org/10.1016/j.bmc.2012.06.054 |
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author | Akdemir, Atilla Edink, Ewald Thompson, Andrew J. Lummis, Sarah C.R. Kooistra, Albert J. de Graaf, Chris de Esch, Iwan J.P. |
author_facet | Akdemir, Atilla Edink, Ewald Thompson, Andrew J. Lummis, Sarah C.R. Kooistra, Albert J. de Graaf, Chris de Esch, Iwan J.P. |
author_sort | Akdemir, Atilla |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3460237 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Elsevier Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34602372012-10-16 Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain Akdemir, Atilla Edink, Ewald Thompson, Andrew J. Lummis, Sarah C.R. Kooistra, Albert J. de Graaf, Chris de Esch, Iwan J.P. Bioorg Med Chem Article 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. Elsevier Science 2012-10-01 /pmc/articles/PMC3460237/ /pubmed/22959526 http://dx.doi.org/10.1016/j.bmc.2012.06.054 Text en © 2012 Elsevier Ltd. https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license |
spellingShingle | Article Akdemir, Atilla Edink, Ewald Thompson, Andrew J. Lummis, Sarah C.R. Kooistra, Albert J. de Graaf, Chris de Esch, Iwan J.P. Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain |
title | Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain |
title_full | Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain |
title_fullStr | Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain |
title_full_unstemmed | Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain |
title_short | Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain |
title_sort | identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460237/ https://www.ncbi.nlm.nih.gov/pubmed/22959526 http://dx.doi.org/10.1016/j.bmc.2012.06.054 |
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