Abstract
In the design of anesthetics, the elucidation of molecular targets and their mechanisms of action are essential. The GABAA receptor is known to be an important molecular target involved in producing loss of consciousness. However, the precise anesthetic target site and its characteristics are unclear. To elucidate the characteristics of the anesthetic binding site, we used the nicotinic acetylcholine (nACh) receptor as a model, as it is in the same superfamily as the GABAA receptor, and the two receptors share a similar structure. In this study, we specifically examined the binding and molecular interactions of barbital enantiomers with the nACh receptor. We used docking simulation to study the binding mode (position, orientation, conformation) of amobarbital, and barbital enantiomers (isobarbital, pentobarbital) with the nACh receptor in its resting state. The nACh receptor structure was obtained from the Protein Data Bank. For flexible docking, the ASEDock 2005 program of the Molecular Operating Environment system was used. Amobarbital docked to the agonist binding site and channel pore of the nACh receptor. (R)- and (S)-isobarbital, and (R)- and (S)-pentobarbital docked to the agonist binding site, and R and S enantiomers docked to positions where the barbital rings were almost superimposed. In a situation where the dominant enantiomeric binding originates from its substructure without chiral point, the enantiomeric contribution to molecular discrimination turns out to be relatively small even if it contains chiral carbon. In this study, the major binding interactions between drug and the receptor were from barbital ring binding. Steric structural differences from chirality of the alkyl side chain did not produce large differences in drug binding forces. Similarly in the anesthetic action site, chiral carbon of the side chain of barbitals may not produce large differences in binding force, as these interactions are the nature of barbital structures. This implies that the barbital anesthetic binding site has no strict selectivity in discriminating between R and S enantiomers.
