TY - JOUR

T1 - Docking to flexible nicotinic acetylcholine receptors

T2 - a validation study using the acetylcholine binding protein

AU - Sander, Tommy

AU - Bruun, Anne T

AU - Balle, Thomas

N1 - Copyright © 2010 Elsevier Inc. All rights reserved. Keywords: protein flexibility; molecular docking; ensemble generation; nicotinic; acetylcholine receptors>; nAChR; acetylcholine binding protein; AChBP

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1016/j.jmgm.2010.08.004

DO - 10.1016/j.jmgm.2010.08.004

M3 - Journal article

C2 - 20884263

VL - 29

SP - 415

EP - 424

JO - Journal of Molecular Graphics and Modelling

JF - Journal of Molecular Graphics and Modelling

SN - 1093-3263

IS - 3

ER -