The major thrust of the research component of my academic practice is the clinically relevant study of molecular mechanisms of alcohol and anesthetic action. While an anesthesia resident at Stanford, I applied the methods of theoretical chemistry to the study of anesthetic mechanisms. This resulted in an initial abstract for a “Computers in Anesthesia” conference in 1992, which remains among the first publications describing the application of computational chemistry to the study of anesthetic mechanisms. This also opened the door for pursuing this line of research further as an ICU fellow. Since then, I have been able to set up my own hardware and software resources for our molecular modeling lab at the Palo Alto VA Hospital, and have developed a very productive collaboration with Dr. Jim Trudell, Professor of Chemistry in Anesthesia in the Stanford University Department of Anesthesia.
Dr. Trudell and I count ourselves fortunate to be among the handful of individuals in the world who are actively and successfully applying the very specialized and cutting-edge techniques of structural biology, protein bioinformatics, molecular modeling, and computational chemistry to the study of anesthetic and alcohol mechanisms. The NIH, the Department of Veterans Affairs and Stanford University have sponsored us.
Our most recent works have led to a detailed quantum mechanical description of anesthetic-protein interactions, as well as a better understanding of large-scale ion channel gating motions through the use of normal mode and molecular dynamics analyses. We now have a model of an anesthetic binding site within the gamma amino butyric acid (GABA) receptor from which we have successfully made predictions of anesthetic activity in compounds not formerly known to be anesthetics, resulting in formal patent filings. While we conducted preliminary tests in vivo, we now wish to proceed to lead compound refinement, detailed mechanistic studies of these compounds within brain slice preparation, and in vitro patch clamp ion channel testing, as well as expand animal testing into mammals. We hope to not only better define the workings of these ion channels that are linked to anesthetic states, but also to design a safer anesthetic for the most vulnerable of our patients. Ultimately, our work should lend itself to a greater understanding of human consciousness and provide an updated perspective of the human condition.