Alchemical Free Energy Perturbation Predicts Relative Binding Affinities of Propofol Analogs and Etomidate Stereoisomers at the GABAAR
Abstract
General anesthetics such as propofol and etomidate exert their clinical effects primarily through positive allosteric modulation of γ-aminobutyric acid type A receptors (GABAAR). Despite decades of research, the quantitative structure-activity relationships governing anesthetic binding remain incompletely characterized at the atomic level. Here, we employ rigorous alchemical free energy perturbation (FEP) calculations using a CHARMm GPU-accelerated protocol to compute relative binding free energies for a series of 13 propofol analogs at the wild-type GABAAR, as well as for the stereoisomeric pair of etomidate (R-etomidate vs S-etomidate). For propofol analogs at the wild-type receptor, computed relative binding free energies (ΔΔG) correlate with experimentally measured GABA EC 50 potentiation values, with propofol (2,6-diisopropylphenol) and disec-butylphenol predicted as the most potent analogs, consistent with experimental data (Pearson r = 0.85, 95% CI 0.50-0.96, p = 0.001; mean of three independent runs). For etomidate, FEP calculations correctly predict that R-etomidate binds approximately 1.8 kcal/mol more favorably than S-etomidate, corresponding to a ∼10-fold difference in potency consistent with the known stereoselective pharmacology of this agent. These results demonstrate that alchemical FEP calculations, implemented through a standardized computational protocol, can quantitatively rank-order anesthetic binding affinities and discriminate stereoisomeric…
Read the paper
Related studies
- eggNOG 5.0: a hierarchical, functionally and phylogenetically annotated orthology resource based on 5090 organisms and 2502 viruses
- Online Survival Analysis Software to Assess the Prognostic Value of Biomarkers Using Transcriptomic Data in Non-Small-Cell Lung Cancer
- OptiType: precision HLA typing from next-generation sequencing data
- Nicotinic Cholinergic System and COVID-19: In Silico Identification of an Interaction between SARS-CoV-2 and Nicotinic Receptors with Potential Therapeutic Targeting Implications
- Saccharomyces cerevisiae cells have three Omega class glutathione S-transferases acting as 1-Cys thiol transferases
- Hemolysis at low blood flow rates: in-vitro and in-silico evaluation of a centrifugal blood pump
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.