Publications
• B.S. 1960, Washington State University
• Ph.D. 1966, University of Wisconsin - Madison
Research Interests
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.
Prof. Grunewald was elected a Fellow of the American Association for the Advancement of Science (AAAS), and has served as chair of the AAAS Pharmaceutical Sciences Section (1994). He was elected an
inaugural member of the Hall of Fame of the American Chemical Society’s Division of Medicinal Chemistry (2006), and has served as division chair (1994) and division councilor (1999–2001). Prof. Grunewald has also served as Chair of the KU Department of Medicinal Chemistry (1994–2003).
The figure above illustrates the binding interactions in the active site of human PNMT with the inhibitor
7-N-(2,2,2-trifluoroethyl)-aminosulfonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (hPNMT K i = 23 nM).
Yellow lines indicate possible hydrogen bonds. Carbons are shown in white, nitrogens in blue, oxygens in red, and sulfur in
yellow. This picture was developed using x-ray crystallographic and molecular modeling techniques.
For More Information, Please Contact:
Dr. Gary Grunewald
1251 Wescoe Hall Dr.
4060a Malott Hall
Tel: 785-864-4497
FAX: 785-864-5326
Email:
ggrunewald@ku.edu
