Docking to flexible nicotinic acetylcholine receptors: a validation study using the acetylcholine binding protein
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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.
Originalsprog | Engelsk |
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Tidsskrift | Journal of Molecular Graphics and Modelling |
Vol/bind | 29 |
Udgave nummer | 3 |
Sider (fra-til) | 415-424 |
ISSN | 1093-3263 |
DOI | |
Status | Udgivet - 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
- Det tidligere Farmaceutiske Fakultet
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ID: 22431800