Docking to flexible nicotinic acetylcholine receptors: a validation study using the acetylcholine binding protein

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

  • Tommy Sander
  • Anne T Bruun
  • Thomas Balle
Computational docking to nicotinic acetylcholine receptors (nAChRs) and other members of the Cys-loop receptor family is complicated by the flexibility of the so-called C-loop. As observed in the large number of published crystal structures of the acetylcholine binding protein (AChBP), a structural surrogate and homology modeling template for the nAChRs, the conformation of this loop is controlled by the ligand present in the binding pocket. As part of the development of a protocol for unbiased docking to the nAChRs, we here present the results of docking of ligands with known binding modes to an AChBP ensemble with systematic variations in C-loop closure generated via a series of targeted geometry optimizations. We demonstrate the ability to correctly predict binding modes for 12 out of 15 ligands and induced degrees of C-loop closure for 14 out of 15 ligands. Our approach holds a promising potential for structure based drug discovery within nAChRs and related receptors.
OriginalsprogEngelsk
TidsskriftJournal of Molecular Graphics and Modelling
Vol/bind29
Udgave nummer3
Sider (fra-til)415-424
ISSN1093-3263
DOI
StatusUdgivet - 2010

Bibliografisk note

Copyright © 2010 Elsevier Inc. All rights reserved.
Keywords: protein flexibility; molecular docking; ensemble generation; nicotinic; acetylcholine receptors>; nAChR; acetylcholine binding protein; AChBP

ID: 22431800