Molecular modelling of specific and non-specific anaesthetic interactions.
There has been rapid progress in molecular modelling in recent years. The convergence of improved software for molecular mechanics and dynamics, techniques for chimeric substitution and site-directed mutations, and the first x-ray structures of transmembrane ion channels have made it possible to build and test models of anaesthetic binding sites. These models have served as guides for site-directed mutagenesis and as starting points for understanding the molecular dynamics of anaesthetic-site interactions. Ligand-gated ion channels are targets for inhaled anaesthetics and alcohols in the central nervous system. The inhibitory strychnine-sensitive glycine and gamma-aminobutyric acid type A receptors are positively modulated by anaesthetics and alcohols; site-directed mutagenesis techniques have identified amino acid residues important for the action of volatile anaesthetics and alcohols in these receptors. Key questions are whether these amino acid mutations form part of alcohol- or anaesthetic-binding sites or if they alter protein stability in a way that allows anaesthetic molecules to act remotely by non-specific mechanisms. It is likely that molecular modelling will play a major role in answering these questions.
Trudell
J R
JR
Department of Anaesthesia, Beckman Program for Molecular and Genetic Medicine, Stanford University, Stanford, CA 94305-5117, USA.
Bertaccini
E
E
D000777:Anesthetics / Q000493:pharmacokinetics*; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D008051:Lipid Bilayers; D008958:Models, Molecular
D000777:Anesthetics; D018685:Anesthetics, Inhalation; D007473:Ion Channels; D008051:Lipid Bilayers; D006221:Halothane