Use of acetylcholine binding protein in the search for novel alpha7 nicotinic receptor ligands. In silico docking, pharmacological screening, and X-ray analysis

C. Ulens, A. Akdemir, A. Jongejan, R. van Elk, S. Bertrand, A. Perrakis, R. Leurs, A.B. Smit, T.K. Sixma, D. Bertrand, I.J.P. de Esch

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Acetylcholine binding protein (AChBP) is widely considered as a functional and structural homologue of the ligand binding domain of Cys-loop receptors. We report the use of AChBP as template to identify ligands for the nicotinic receptors (nAChRs). An in silico screening protocol was set up and applied to crystal structures of AChBP. Several ligands containing a dibenzosuberyl moiety were identified and shown to bind with high affinity to AChBP and α7 nAChRs. Two high affinity ligands were cocrystallized with AChBP, revealing the binding mode in the orthosteric site. Functional studies revealed that these two ligands caused inhibition of the α7, α4β2, and 5HT
Original languageEnglish
Pages (from-to)2372-2383
Number of pages11
JournalJournal of Medicinal Chemistry
Volume52
DOIs
Publication statusPublished - 2009

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