General Anesthetic Binding Mode Via Hydration with Weak Affinity and Molecular Discrimination: General Anesthetic Dissolution in Interfacial Water of the Common Binding Site of GABA Receptor

Overview

Journal Biophys Physicobiol

Specialty Biophysics

Date 2024 Mar 18

PMID 38496235

Authors

Tomoyoshi Seto

Affiliations

Soon will be listed here.

Abstract

The GABA receptor (GABAR) is a target channel for the loss of awareness of general anesthesia. General anesthetic (GA) spans a wide range of chemical structures, such as monatomic molecules, barbital acids, phenols, ethers, and alkanes. GA has a weak binding affinity, and the affinity has a characteristic that correlates with the solubility in olive oil rather than the molecular shape. The GA binding site of GABAR is common to GAs and exists in the transmembrane domain of the GABAR intersubunit. In this study, the mechanism of GA binding, which allows binding of various GAs with intersubunit selectivity, was elucidated from the hydration analysis of the binding site. Regardless of the diverse GA chemical structures, a strong correlation was observed between the binding free energy and total dehydration number of the binding process. The GA binding free energy was more involved in the binding dehydration and showed molecular recognition that allowed for the binding of various GA structures via binding site hydration. We regarded the GA substitution for the interfacial water molecule of the binding site as a dissolution into the interfacial hydration layer. The elucidation of the GA binding mechanism mediated by hydration at the GABAR common binding site provides a rationale for the combined use of anesthetics in medical practice and its combination adjustments via drug interactions.

References

Aryal P, Sansom M, Tucker S . Hydrophobic gating in ion channels. J Mol Biol. 2014; 427(1):121-30. PMC: 4817205. DOI: 10.1016/j.jmb.2014.07.030. View

Olsen R, Sieghart W . GABA A receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology. 2008; 56(1):141-8. PMC: 3525320. DOI: 10.1016/j.neuropharm.2008.07.045. View

Jayakar S, Zhou X, Chiara D, Jarava-Barrera C, Savechenkov P, Bruzik K . Identifying Drugs that Bind Selectively to Intersubunit General Anesthetic Sites in the 132 GABAR Transmembrane Domain. Mol Pharmacol. 2019; 95(6):615-628. PMC: 6505378. DOI: 10.1124/mol.118.114975. View

Gerber P, Muller K . MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry. J Comput Aided Mol Des. 1995; 9(3):251-68. DOI: 10.1007/BF00124456. View

Franks N . Molecular targets underlying general anaesthesia. Br J Pharmacol. 2006; 147 Suppl 1:S72-81. PMC: 1760740. DOI: 10.1038/sj.bjp.0706441. View

Laverty D, Desai R, Uchanski T, Masiulis S, Stec W, Malinauskas T . Cryo-EM structure of the human α1β3γ2 GABA receptor in a lipid bilayer. Nature. 2019; 565(7740):516-520. PMC: 6364807. DOI: 10.1038/s41586-018-0833-4. View

Brown E, Pavone K, Naranjo M . Multimodal General Anesthesia: Theory and Practice. Anesth Analg. 2018; 127(5):1246-1258. PMC: 6203428. DOI: 10.1213/ANE.0000000000003668. View

Urban B . The site of anesthetic action. Handb Exp Pharmacol. 2008; (182):3-29. DOI: 10.1007/978-3-540-74806-9_1. View

Ueda I, Mashimo T . Anesthetics expand partial molal volume of lipid-free protein dissolved in water: electrostriction hypothesis. Physiol Chem Phys. 1982; 14(2):157-64. View

10.

Imai T, Hiraoka R, Kovalenko A, Hirata F . Water molecules in a protein cavity detected by a statistical-mechanical theory. J Am Chem Soc. 2005; 127(44):15334-5. DOI: 10.1021/ja054434b. View

11.

Imai T, Isogai H, Seto T, Kovalenko A, Hirata F . Theoretical study of volume changes accompanying xenon-lysozyme binding: implications for the molecular mechanism of pressure reversal of anesthesia. J Phys Chem B. 2006; 110(24):12149-54. DOI: 10.1021/jp056346j. View

12.

Johnson F, FLAGLER E . Hydrostatic pressure reversal of narcosis in tadpoles. Science. 1950; 112(2899):91-2. DOI: 10.1126/science.112.2899.91-a. View

13.

Woll K, Zhou X, Bhanu N, Garcia B, Covarrubias M, Miller K . Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors. FASEB J. 2018; 32(8):4172-4189. PMC: 6044061. DOI: 10.1096/fj.201701347R. View

14.

King E, Aitchison E, Li H, Luo R . Recent Developments in Free Energy Calculations for Drug Discovery. Front Mol Biosci. 2021; 8:712085. PMC: 8387144. DOI: 10.3389/fmolb.2021.712085. View

15.

Belrose J, Noppens R . Anesthesiology and cognitive impairment: a narrative review of current clinical literature. BMC Anesthesiol. 2019; 19(1):241. PMC: 6933922. DOI: 10.1186/s12871-019-0903-7. View

16.

Goto J, Kataoka R, Muta H, Hirayama N . ASEDock-docking based on alpha spheres and excluded volumes. J Chem Inf Model. 2008; 48(3):583-90. DOI: 10.1021/ci700352q. View

17.

Rengel K, Pandharipande P, Hughes C . Postoperative delirium. Presse Med. 2018; 47(4 Pt 2):e53-e64. DOI: 10.1016/j.lpm.2018.03.012. View

18.

Labute P . The generalized Born/volume integral implicit solvent model: estimation of the free energy of hydration using London dispersion instead of atomic surface area. J Comput Chem. 2008; 29(10):1693-8. DOI: 10.1002/jcc.20933. View

19.

Koelblinger P, Thuerigen O, Dummer R . Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018; 30(2):125-133. PMC: 5815646. DOI: 10.1097/CCO.0000000000000426. View

20.

Sebel L, Richardson J, Singh S, Bell S, Jenkins A . Additive effects of sevoflurane and propofol on gamma-aminobutyric acid receptor function. Anesthesiology. 2006; 104(6):1176-83. DOI: 10.1097/00000542-200606000-00012. View