Clinical Focus

  • Anesthesia

Academic Appointments

Professional Education

  • Residency:Stanford University Hospital - Anesthesia Dept (2016) CA
  • Internship:Weill Cornell Medical College of Cornell University (2013) NY
  • Medical Education:Indiana University School of Medicine (2012) IN

All Publications

  • Insights Into Receptor-Based Anesthetic Pharmacophores and Anesthetic-Protein Interactions. Methods in enzymology Fahrenbach, V. S., Bertaccini, E. J. 2018; 602: 77–95


    General anesthetics are thought to allosterically bind and potentiate the inhibitory currents of the GABAA receptor through drug-specific binding sites. The physiologically relevant isoform of the GABAA receptor is a transmembrane ligand-gated ion channel consisting of five subunits (gamma-alpha-beta-alpha-beta linkage) symmetrically arranged around a central chloride-conducting pore. Although the exact molecular structure of this heteropentameric GABAA receptor remains unknown, molecular modeling has allowed significant advancements in understanding anesthetic binding and action. Using the open-channel conformations of the homologous glycine and glutamate-gated chloride receptors as templates, a homology model of the GABAA receptor was constructed using the Discovery Studio computational chemistry software suite. Consensus structural alignment of the homology templates allowed for the construction of a three-dimensional heteropentameric GABAA receptor model with (gamma2-beta3-alpha1-beta3-alpha1) subunit linkage. An anesthetic binding site was identified within the transmembrane alpha/beta intersubunit space by the convergence of three residues shown to be essential for anesthetic activity in previous studies with mutant mice (beta3-N265, beta3-M286, alpha1-L232). Propofol derivatives docked into this binding site showed log-linear correlation with experimentally derived GABAA receptor potentiation (EC50) values, suggesting this binding site may be important for receptor activation. The receptor-based pharmacophore was analyzed with surface maps displaying the predominant anesthetic-protein interactions, revealing an amphiphilic binding cavity incorporating the three residues involved in anesthetic modulation. Quantum mechanics calculations of the bonding patterns found in complementary high-resolution receptor systems further elucidated the complex nature of anesthetic-protein interactions.

    View details for DOI 10.1016/bs.mie.2018.01.004

    View details for PubMedID 29588042