Comparative studies on the binding site of anesthetics to GABA a receptors using in silico docking methods

Abstract

Background: Although the GABAA receptor (GABAAR) has been proposed as the main action site for sevoflurane, isoflurane, halothane, enflurane, propofol, and benzodiazepines (BZDs), binding of these anesthetics with high-resolution structures of the GABAAR have been rarely examined by comparative docking analyses. Moreover, various combinations of ligands on more GABAARs with various subtypes need to be analyzed to understand the elaborate action mechanism of GABAARs better because some GABAA ligands showed specificity toward the distinct subtypes of the GABAAR.

Methods: We performed in silico docking analysis to compare the binding modes of sevoflurane, isoflurane, halothane, enflurane, propofol, and BZDs to the GABAAR based on one of the most recently provided 3D structures. We performed the docking analysis and the affinity-based ranking of the binding sites.

Results: Our docking studies revealed that isoflurane, halothane, and enflurane docked in an extracellular domain (ECD) on GABAARs, in contrast to sevoflurane. Conclusion: Our results supported a multi-site mechanism for the allosteric modulation of propofol. Propofol was bound to the pore or favored various subsites in the transmembrane domain (TMD). Our result confirmed that different chemically related BZD ligands interact via distinct binding modes rather than by using a common binding mode, as previously suggested.