Purpose: The mission of the Medicinal Chemistry Group at the GRI Drug Discovery Center is to facilitate the design and development of molecular entities as probes of disease mechanisms and as potential therapeutic agents for these diseases. Medicinal chemistry involves combination of the disciplines of synthetic organic chemistry, molecular modeling, computational biology, structural genomics, and pharmacology to design new drugs, and investigate their interactions with biological targets at the molecular, cellular, and whole-animal level. Through close collaboration with biologists at the GRI, it is anticipated that rapid identification of molecular targets via genomic techniques coupled with state-of-the-art computational and synthetic methods will shortened the lead time for development of candidate molecules for treatment of various disease states. At this time, the emphasis is on the development of agents for the treatment of cancer, obesity and heart disease. Current targets are ligands that interact with G-coupled protein receptors (e.g. melanocortins, neuropeptide-Y, & glucocorticoid-induced receptor) and protein kinases (e.g. mTOR, PI3Ka, calmodulin activated protein kinase 2 [CaMKII], & Akt). As the core medicinal chemistry group expands additional target systems will be identified and exploited.

Approach: Drug design and development is an iterative process requiring close collaboration between the biologists who understand the target system and have developed assays to study it, and the chemists who design and synthesize molecules to influence the behavior of the target. Coupled with this is the use of molecular modeling techniques to study how compounds interact with the target molecule's active site. Structural information on the target can provide a basis for identifying key sites of interactions (active or allosteric sites) and then designing compounds to make those key interactions. Generally the models are based on X-ray crystal structures of the target protein. However, often, such a structure is not available. In this event, a homology model is built based on sequence homology of the target protein with closely related proteins where an X-ray crystal structure has been solved. In addition, a number of ligand based modeling approaches exist to assist in the design of novel molecules which mimic the key interactions of known ligands, but posees enhanced other properties, such as selectivity, permeability or metabolic profiles.

With a model of the target protein in hand, the chemist design a molecule to be a potential inhibitor based upon virtual docking experiments, comparing to known substrates, or by virtual screening of compound libraries to find molecules that interact with it. Once a structure of interest is determined, it is then synthesized and tested on the target protein in an in vitro assay. Compounds that show promise then enter an iterative design and test loop to optimize their target activity, selectivity and cellular activity. Along with optimization of the molecule for interaction with the target protein, the chemist also must keep in mind the structural and physical chemical properties of the molecule to ensure they are appropriate for water solubility, oral absorption, distribution to the target site in the organism, metabolism, and do not contain functionalities associated with toxicity.

Faculty: The medicinal chemistry group currently consists of four senior faculty members: Eric Hu, James Knittel, William Seibel and Matt Wortman.

Dr. Eric Hu, Visiting Associate Professor: Dr. Hu brings over 12 years of industrial medicinal chemistry experience to the group. He has been involved in the design and synthesis of small molecules and peptidomimetics as antibacterials and anti-obesity agents. He is currently collaborating in Prof. Knittel's group working on developing methods for synthesizing phosphorylated peptide fragments of osteopontin, and protein involved facilitating metastisis in breast cancer.

Dr, James J. Knittel, Associate Professor: Dr. Knittel has 25 years of experience in the design and synthesis of agonist and antagonists of peptide hormones and neurotransmitters. He has worked with cholecystokinin, neuropeptide-Y, peptide-YY and melanocortins. His group is involved with the design and synthesis un-natural amino acids for incorporation into these peptides as well as methods for conformational restriction to determine their bioactive conformations. In addition, Dr. Knittel's group is involved in developing inhibitors for PI3Ka and CamKIId. All of these projects involve the use of X-ray crystal structures and construction of homology models to perform virtual docking and library screening for finding small molecule inhibitors of these targets.

Dr. William Seibel, Research Associate Professor & Director of Medicinal Chemistry and Compound Repository Services: Dr. Seibel has 20 years of experience in the pharmaceutical industry and has led groups in the design and development of antibacterials, cardiovascular drugs, and anti-obesity agents. This work included optimization of known classes of drugs (e.g. quinolones, beta lactams, α₂ agonists), and explorations into emerging targets in disease (e.g. melanocortin receptors, phosphatases, aminopeptidases). He has also led groups responsible for combinatorial chemistry, computational chemistry and structural biology, and currently oversees the operation of the Drug Discovery UC Compound Repository, a collection of over 250,000 drug-like compounds.

Dr. Matt Wortman, Research Associate Professor & Director of Computational Biology & Information Technology: Dr. Wortman is responsible for oversight of the computational infrastructure and capabilities of the GRI. This includes constructing molecular models of target proteins, collaborating with chemists' virtual screening of compound libraries, and the use of ligand based methods to design agents from known substrates and inhibitors of the targets.

Additional Personnel: Currently there are two graduate students (Philip Cherian & Andrew Ruwe) and one technician level synthetic chemist (Ms. Ritu Tiku) also in the group.

Facilities: The medicinal chemistry group occupies four state of the art synthetic laboratories able to accommodate 15 – 20 medicinal chemists. The labs are equipped with analytical and preparative HPLC systems, CreoSalus Tetras parallel multiple peptide synthesizer, LC-MS, 300 MHz NMR, and LINUX and Windows based computer workstations with molecular modeling, computational chemistry and bioinformatics software. The GRI also has a high-speed connection the Ohio State University super computer center via the Third Frontier Network for intensive modeling calculations.

Contact: William L. Seibel, Ph.D.
Director of Medicinal Chemistry and Compound Repository
Research Associate Professor
Genome Research Institute
University of Cincinnati
2180 East Galbraith Rd.
Cincinnati, OH 45237

William.Seibel@uc.edu

James J. Knittel, Ph.D.
Associate Professor
College of Pharmacy
Genome Research Institute
University of Cincinnati
2180 East Galbraith Rd.
Cincinnati, OH 45237
Tel. 513 558-0733
Jim Knittel