Determining the binding site of Carisoprodol on GABAA receptor




Liu, Jin
Hayatshahi, Sayyed
Huang, Renqi
Claudio, Maria


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Purpose: Carisoprodol (CSP) is prescribed to treat musculoskeletal pain. CSP exerts inhibitory action on GABAA receptors (GABAA Rs) in certain concentrations. However, its binding sites remain elusive. The purpose of this study is to determine the binding site for CSP's inhibitory action on GABAA Rs. Our electrophysiological studies have shown that CSP inhibitory action is diminished by alpha1 T261F mutation of the picrotoxin (PTX) binding site. Therefore, we hypothesize that CSP shares PTX's binding site at GABAA Rs. Methods: We docked CSP on wild type alpha1beta2gamma2 and mutant alpha1(T261F)beta2gamma2 GABAA Rs using Glide program. We further performed molecular dynamics (MD) simulations of wild type and mutant GABAA Rs in unbound forms and in complex with PTX and CSP. Results: The docking reproduced the experimental pose of PTX and the effect of mutations on its binding, but could not predict the effect of the mutations on the CSP binding. However, the MD simulations showed that the local channel conformation is changed upon the mutations, and consequently, the binding of both ligands is significantly deteriorated. We further used the observed receptor-ligand interactions of CSP to predict molecular changes that would improve its binding. Conclusions: We demonstrate that the consideration of the pocket dynamics is necessary to capture the changes mutations potentially cause in GABAA Rs. The similar trend for CSP and PTX in MD simulation results validate our hypothesis that the two molecules share the same binding pocket. These data provide further information on how CSP may interact with the receptors.