Molecular Discrimination of Barbital Enantiomer at the Propofol Binding Site of the Human β₃ Homomeric GABA_A Receptor

Abstract

Intravenous anesthetic barbitals act on the GABA_A receptor, and this receptor is the principal molecular target of loss of consciousness. Their action and side effects differ according to the enantiomer. Elucidation of their enantiomeric action is essential for a safe anesthetic agent. This study investigates molecular mechanisms of discrimination of enantiomeric barbital in the binding site of the GABA_A receptor. Amobarbital, (R)-, (S)-pentobarbital, and (R)-, (S)-isobarbital bonded to the TM2-TM2’ transmembrane domain (TMD), i.e., the propofol binding site. There was a 2.9 kcal mol^_-1 difference in enantiomeric pentobarbital bindings. Pentobarbital discrimination in the TM2-TM2’ TMD site was caused not only by the barbital ring’s hydrogen-bond, but also by steric fittings of the methyl-group adjacent to the chiral carbon atom.