Gary Grunewald's research focused on drug design and using computer modeling and NMR techniques, mechanism of drug action in the central nervous system, enzyme inhibitors and neurotransmitters.
His research group studied the three-dimensional shape of drugs required for interaction with target sites (receptors, enzymes). 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. Grunewald's work also included the 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. 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. The Grunewald research group simultaneously mapped the desired active site of the enzyme PNMT and the undesired competing binding site, the a2-adrenoceptor, to achieve this success.