Dr. Gary Grunewald did his undergraduate work in pharmacy at Washington State University and obtained his Ph.D. from the University of Wisconsin.
Drug design using computer modeling and NMR techniques, mechanism of drug action in the central nervous system, enzyme inhibitors, and neurotransmitters.
Studies of the three-dimensional shape of drugs required for interaction with target sites (receptors, enzymes) have been a major focus of the work of Prof. Grunewald's research group. For many flexible drug molecules, one conformation is preferentially required for the desired action at a receptor site, and a different low-energy conformation is responsible for side effects through action at a second site.
Synthesis of analogues in which the molecular framework of the pharmacophore of the drug is "locked" into a conformationally-restricted (semi-rigid) or conformationally-defined (rigid) system allows a careful study of conformational aspects of drug action. In order to determine the function of epinephrine in the central nervous system, selective inhibitors of phenylethanolamine N-methyltransferase (PNMT) are required. Coupled with high-field NMR techniques, such as transferred nuclear Overhauser enhancements, and molecular modeling using computational techniques for pharmacophore delineation, a potent and selective inhibitor of epinephrine biosynthesis has recently been synthesized. It was necessary to simultaneously map the desired active site of the enzyme PNMT and the undesired competing binding site, the a2-adrenoceptor, to achieve this success.
Similar drug design approaches are underway for antidepressant drugs (neurotransmitter-selective reuptake inhibitors), anticancer drugs related to paclitaxel (Taxol ™), and NMDA receptor antagonists for the treatment of stroke.