Similarly, stereo- and regioselective synthesis of epoxides derived from carcinogenic polycyclic hydrocarbons and spectroscopic analysis of DNA adducts allow for a more detailed understanding of DNA damage at the molecular level. Newly developed methods are employed in research on the synthesis of a variety of natural products such as podophyllotoxin, physostigmine, swainsonine and related pyrolizidine alkaloids, lycorane, crinine, augustamine, tylophorine, and amabiline, all of which have potential application as drugs for the treatment of human diseases. The development of stereoselective cyclization strategies for the synthesis of artificial transcription factors is also an ongoing effort. The wide variety of synthetic organic chemistry being investigated in U-M's Medicinal Chemistry program enables students to receive excellent training in organic synthesis while learning the biochemical aspects of drug design and evaluation.

Specific areas of research interest include the enzymology of co-translational glycosylation of proteins, post-transciptional modification of RNA, and bacterial cell wall biosynthesis. The synthesis and biochemistry of novel amino acids and peptides as anti-folates and opioids are also active research areas. The role of G-protein-coupled receptors in signal transduction involving opioids involves the interface of computational methods with biochemical pharmacology. Thus, students interested in the biochemical aspects of drug design and action can carry out research on some of the most exciting topics in contemporary biology while obtaining excellent training in a rigorous, chemistry-based program.

The research groups of Drs. Coward and Woodard combine the use of stable-labeled compounds and 13C, 19F, 31P, and 17O-NMR spectroscopy to investigate cryptic mechanisms of pharmacologically important enzymes. Dr. Mosberg and his group utilize NMR for conformational analysis of conformationally restricted opioid peptides and receptor fragments in combination with their computational studies to gain insight into the potential three-dimensional structure of target molecules. Drs. Coward and Mapp and their groups follow the progress of their synthesis efforts via high field NMR.

Several groups utilize the technique of MS-MS to elucidate the composition of peptides as well as proteolyticly-digested proteins. The laboratories of Coward, Garcia, Mapp and Woodard utilize standard UV and fluorescence spectroscopy for various spectral assays of the enzymes under study. In addition, Garcia's and Mapp's laboratories utilize temperature-ramped UV spectroscopy in their studies of tRNA and oligoribonucleotides as well as oligonucleotides. Rapid-reaction techniques are being used to isolate intermediates from very fast reactions as well as to gain structural information concerning the transiently formed intermediates. In particular, rapid-quench cooling experiments designed to visualize transient intermediates using solution and solid-state NMR on the quenched samples in the Woodard group are also underway. Several groups are also involved in the use of x-ray crystallography to determine the overall structure of proteins under study in their laboratories.

Creating new computational methods is among the most important contributions of these research groups. Novel approaches are being developed for protein folding, cheminformatics, structure-based drug design, and the prediction of ligand-protein complexes. The Carlson group focuses on understanding the biophysics of molecular recognition and the fundamental nature of proteins and drug-like molecules. The emphasis in the Crippen group is on developing methods for quantitative structure-activity relations in the absence of a receptor structure and on statistical mechanical theories for protein folding. The Mosberg group is focused primarily on designing inhibitors and protein models of membrane-bound proteins such as G-protein-coupled receptors and the ABC family of transporters. Wang's group focuses on developing new computational methods for structure-based design, protein folding, and bioinformatics; they also use this software in the discovery and design of novel small molecule drugs for treatment of cancer and neurological diseases.

Dr. Coward's group is involved in evaluation of new compounds for their ability to deplete intracellular folates or antifolates and thereby alter folate-dependent one-carbon metabolism or cancer cell toxicity, respectively. Other new compounds are evaluated as anti-cancer and anti-parasitic drugs in appropriate cell culture systems. Dr. Drach's research involves the search for new compounds with antiviral activity against herpesviruses and human immunodeficiency virus. This involves testing new compounds for their capacity to block viral replication as well as for their cytotoxicity to uninfected normal and cancer cells. Dr. Woodard's group is using high throughput screening (HTS) to find better antibiotics using an enzyme involved in LPS biosynthesis as the screen. They also have a second series of compounds whose structure is being modified via examination of the X-ray structure and kinetics of action of the compounds. In each of these groups, once active compounds have been discovered, major research efforts are dedicated to understanding the molecular basis for the modes of actions of new compounds. A number of approaches are used including biochemical, genetic, virological, and animal model studies.