Title:In Silico Modeling of the α7 Nicotinic Acetylcholine Receptor: New Pharmacological Challenges Associated with Multiple Modes of Signaling
VOLUME: 20 ISSUE: 10
Author(s):Alican Gulsevin*, Roger L. Papke and Nicole Horenstein*
Affiliation:Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, FL, 32611-7200, Department of Pharmacology and Therapeutics, University of Florida, P.O. Box 100267, Gainesville, FL 32610, Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, FL, 32611-7200
Keywords:Anti-inflammatory, nAChR, central nervous system, molecular dynamics, Cys-loop, schizophrenia.
Abstract:The α7 nicotinic acetylcholine receptor is a homopentameric ion-channel of the Cys-loop
superfamily characterized by its low probability of opening, high calcium permeability, and rapid desensitization.
The α7 receptor has been targeted for the treatment of the cognitive symptoms of schizophrenia,
depression, and Alzheimer’s disease, but it is also involved in inflammatory modulation as a
part of the cholinergic anti-inflammatory pathway. Despite its functional importance, in silico studies
of the α7 receptor cannot produce a general model explaining the structural features of receptor activation,
nor predict the mode of action for various ligand classes. Two particular problems in modeling
the α7 nAChR are the absence of a high-resolution structure and the presence of five potentially nonequivalent
orthosteric ligand binding sites. There is wide variability regarding the templates used for
homology modeling, types of ligands investigated, simulation methods, and simulation times. However,
a systematic survey focusing on the methodological similarities and differences in modeling α7 has
not been done. In this work, we make a critical analysis of the modeling literature of α7 nAChR by
comparing the findings of computational studies with each other and with experimental studies under
the main topics of structural studies, ligand binding studies, and comparisons with other nAChR. In
light of our findings, we also summarize current problems in the field and make suggestions for future
studies concerning modeling of the α7 receptor.
