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

Atilla Akdemir; Ewald Edink; Andrew J. Thompson; Sarah C.R. Lummis; Albert J. Kooistra; Chris De Graaf; Iwan J.P. De Esch

doi:10.1016/j.bmc.2012.06.054

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

Atilla Akdemir, Ewald Edink, Andrew J. Thompson, Sarah C.R. Lummis, Albert J. Kooistra, Chris De Graaf, Iwan J.P. De Esch^*

^*Corresponding author af dette arbejde

11 Citationer (Scopus)

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 [ ³H]epibatidine on chimeric α7/5-HT₃ 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.

Originalsprog	Engelsk
Tidsskrift	Bioorganic and Medicinal Chemistry
Vol/bind	20
Udgave nummer	19
Sider (fra-til)	5992-6002
Antal sider	11
ISSN	0968-0896
DOI	https://doi.org/10.1016/j.bmc.2012.06.054
Status	Udgivet - 1 okt. 2012
Udgivet eksternt	Ja

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10.1016/j.bmc.2012.06.054Licens: CC BY

pmc3460237?pdf=renderForlagets udgivne version, 2,45 MBLicens: CC BY

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Akdemir, A., Edink, E., Thompson, A. J., Lummis, S. C. R., Kooistra, A. J., De Graaf, C., & De Esch, I. J. P. (2012). Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain. Bioorganic and Medicinal Chemistry, 20(19), 5992-6002. https://doi.org/10.1016/j.bmc.2012.06.054

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. et al.

I: Bioorganic and Medicinal Chemistry, Bind 20, Nr. 19, 01.10.2012, s. 5992-6002.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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

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% (pKi ≥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 [ 3H]epibatidine on chimeric α7/5-HT3 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.",

keywords = "α7 Receptor, AChBP, Cys-loop, Docking, In silico screening, nAChR, Virtual screening",

author = "Atilla Akdemir and Ewald Edink and Thompson, {Andrew J.} and Lummis, {Sarah C.R.} and Kooistra, {Albert J.} and {De Graaf}, Chris and {De Esch}, {Iwan J.P.}",

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AU - Akdemir, Atilla

AU - Edink, Ewald

AU - Thompson, Andrew J.

AU - Lummis, Sarah C.R.

AU - Kooistra, Albert J.

AU - De Graaf, Chris

AU - De Esch, Iwan J.P.

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AB - 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% (pKi ≥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 [ 3H]epibatidine on chimeric α7/5-HT3 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.

KW - α7 Receptor

KW - AChBP

KW - Cys-loop

KW - Docking

KW - In silico screening

KW - nAChR

KW - Virtual screening

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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

Abstract

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