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

Research output: Contribution to journalJournal articleResearchpeer-review

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

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.

Original languageEnglish
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number19
Pages (from-to)5992-6002
Number of pages11
ISSN0968-0896
DOIs
Publication statusPublished - 1 Oct 2012
Externally publishedYes

    Research areas

  • α7 Receptor, AChBP, Cys-loop, Docking, In silico screening, nAChR, Virtual screening

ID: 199376408