Drug Discovery and Medicinal Chemistry

Drug Discovery And Medicinal Chemistry

Medicinal chemistry examines the chemical design of active pharmacological agents through an understanding of the molecular biology of pharmacological targets using quantitative structure activity relationships and computational methods. Compounds are synthesized by innovative medicinal chemistry methodologies. Our faculty’s research emphasizes the discovery and synthesis of antiviral, anticancer, antiprotozoal and antibacterial agents. Investigators use x-ray crystallography to define the atomic-level architecture of potential drug targets and analytical chemistry to detect drugs and drug products in dosage forms through high-performance liquid chromatography, gas chromatography, capillary electrophoresis and mass spectrometry.

Faculty members & their research interests

michael g. bartlett

Michael Bartlett
Professor and Director-BS Program
Georgia Athletic Association Professor in Pharmacy

Interim Assistant Dean for Nontraditional Education and Outreach

Dr. Bartlett’s lab research centers around applications of analytical chemistry to study biological problems. Currently, he and his team are studying the absorption, distribution, metabolism and excretion (ADME) of drug substances and environmental toxicants with the goal of developing novel methods to address significant questions in the biomedical sciences. In collaboration with Dr. James Bruckner, they aim to provide realistic risk assessments for common environmental contaminants. Furthermore, in collaboration with Dr. Alvin V. Terry at the Medical College of Georgia (MCG), they also study many compounds shown to affect memory and cognition, and have developed several highly sensitive assessments to determine overall impact on the brain.

warren beach

Warren Beach
Associate Professor

Dr. Beach’s research interests are in the area of the synthesis of compounds as potential treatments for neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. The current series of compounds studied in his lab (in collaboration with Dr. A.V. Terry of Georgia Health Sciences University) have a number of useful therapeutic properties including cognitive enhancement, increasing attention and decreasing/slowing the development of plaque formation in the mouse model of Alzheimer’s disease.

The elucidation of the mechanism of action of these compounds in ongoing. However, current evidence indicates that they seem to be silent desensitizers. These compounds do not cause the activation of the receptor, but cause the receptor to go into an inactive state (closed and unable to be stimulated). This desensitization leads to an up-regulation of beneficial cascades within the cell.

david chu

David Chu
Distinguished Research Professor, Emeritus

Dr. Chu’s research focuses on nucleoside and carbohydrate chemistry, antiviral chemotherapy (HIV, Hepatitis B & C, West Nile and Epstein-Barr), cancer chemotherapy, structure-based drug design and molecular modeling, and antiviral drug discovery for bioterrorism (Smallpox, Monkeypox, Ebola, etc.).

eileen j. kennedy

Eileen Kennedy
Assistant Professor

The protein kinase superfamily comprises one of the largest gene families encoded in the human genome.  A comprehensive understanding of kinase activity under normal and disease states is critical in order to identify targets for disease intervention.  However, studying kinase signaling is inherently challenging since there are more than 500 kinases in the human genome, and as a result, there is significant crosstalk among multiple kinases for phosphorylation targets.  Additionally, multiple isoforms exist for many kinases, thereby making it nearly impossible to address the question using genetic knockdowns/knockouts since other genes will compensate with altered expression levels.

To address this question, the Kennedy lab is developing novel chemical biology strategies to synthetically disrupt protein:protein interactions (PPIs) using chemically stabilized peptides.  This methodology allows for the development of investigative tools that can be applied to elegantly and selectively manipulate protein-protein interactions that are involved in signaling pathways within a cellular environment.  The long-term goal of the lab is to develop synthetic biologics that can be used to probe cell signaling events that are mediated by kinases.  By inhibiting specific protein:protein interactions within a cellular environment, cancer-related cell signaling events can be studied in a temporal manner and highlight new strategies for therapeutic intervention.  They are applying this strategy to study the AGC family of kinases as well as EGFR in breast and lung cancer models.

dexi liu

Dexi Liu
Department Head
Panoz Professor of Pharmacy

My laboratory is interested in the use of gene/protein as a drug for prevention and treatment of obesity, diabetes, cancer and other diseases. Our emphasis is on identification of genes that code for a therapeutic protein and on illustration of its mechanisms of action. We employ gene cloning, biochemical, cell biological, immunological, and gene delivery/transfer techniques to conduct basic research in cell culture and in animal models.

cory momany

Cory Momany
Associate Professor

Dr. Momany’s research is focused on the application of atomic structures to biological and pharmaceutical problems. The research program is multidisciplinary in approach and bridges the fields of molecular biology, biochemistry, and structure-based drug discovery- all centered around the use of macromolecular X-ray crystallography.

Current funded research is focused on understanding the process of bacterial transcriptional activation at a structural level.  Two families of transcriptional regulators are being studied, the MerR and LysR-type transcriptional regulator family, as model systems.  LTTRs are the largest family of regulators in bacteria, and as such display a wide range of functions spanning nitrogen fixation to virulence.  Our studies have far-reaching applications in the areas of bioremediation and drug discovery.

One ongoing project in the laboratory is the development of new means to produce antibodies for use as new therapeutics and crystallization vehicles.  Large-scale production of antibody therapeutics is possible in bacterial expression systems.  Using powerful in vitro selection systems, new antibodies can be obtained rapidly without using mouse hybridoma technology.  Cocrystallization of proteins with antibodies is a powerful method for crystallizing membrane-associate proteins that are otherwise extremely difficult to study. Another project is focused on the drug discovery for Alzheimer’s disease targeting the kynurenine pathway (tryptophan metabolism).  Using a structure-guided approach, we are designing inhibitors of the pathway that can increase neuroprotective molecules while reducing neurotoxic intermediates.

vasu nair

Vasu Nair
William H. Terry, Sr., Chair-GRA Eminent Scholar
Director, UGA Center for Drug DiscoveryAssociate Dean for Research, College of Pharmacy

Dr. Nair’s research focuses on medicinal chemistry, chemical biology and drug discovery, conceptually new compounds with antiviral activities against DNA and RNA viruses including retroviruses (HIV), and molecules with anticancer activity.

Research efforts in Dr. Nair’s laboratory are concerned with the chemistry and biology of nucleosides, nucleotides and related compounds with particular emphasis on the discovery of novel molecules of antiviral therapeutic interest. Application of molecular recognition concepts to viral genes and enzymes form the basis of our drug design work. Chemoenzymatic methods are utilized for the synthesis of new inhibitors targeted at DNA and RNA viruses, including retroviruses such as HIV. Key enzymes of nucleoside and nucleotide metabolism of interest include deaminases, transferases, kinases, phosphodiesterases, and nucleic acid polymerases. Interdisciplinary antiviral studies are performed through national and international collaborative arrangements.

One example of success in his quest for new antiviral molecules is the discovery of a compound called an isonucleoside that is potently active against retroviruses (lentiviruses). Its triphosphate is one of the most potent known inhibitors of the viral enzyme, HIV reverse transcriptase. A more recent example of success is the discovery of potent inhibitors of HIV integrase. The viral enzyme is involved in the integration of viral DNA into human DNA, the most devastating step in the attack of human cells by HIV. Blocking the biochemical mechanism of action of this enzyme is a logical approach to preventing this viral DNA invasion of the human system. Dr. Nair’s laboratory has discovered stable (i.e., nuclease-resistant), conceptually-novel dinucleotides (miniature surrogate DNA molecules) that are recognized by wild-type HIV integrase and that have strong inhibitory activity against the viral enzyme. In more recent work, they have designed and synthesized novel molecules constructed on nucleobase scaffolds that inhibit both steps of HIV integrase action. A few of these compounds have been found to exhibit highly potent anti-HIV activity. Other investigations in his laboratory have focused on drug discovery against infectious RNA viruses, with particular emphasis on the virus families, paramyxoviridae, flaviviridae and filoviridae. The enzyme, IMPDH, is used as a probe for RNA antiviral drug discovery.

scott d. pegan

Scott Pegan
Associate Professor

Discovery of new antibiotics for use against Tuberculosis

Tuberculosis (TB) is one of the most prevalent infections in the world, and a leader among the causes of mortality in developing countries. The World Health Organization estimates one third of the world’s population is infected with latent TB. With a rise in new cases of active TB and emergence of multidrug resistant strains, MDR-TB and XDR-TB, there is a strong need for development of antibiotics targeting novel pharmacological targets within Mycobacterium tuberculosis. One such drug target for TB is M. tuberculosis’ class II fructose 1,6-bisphosphate aldolase (MtFBA), which is required for bacterial survival and is non-existent in humans. Inhibitors have been developed for class II FBAs; however, they lack specificity and drug-like properties, preventing their translation into viable therapeutic leads. Optimization of these compounds has been historically hindered by a lack of MtFBA structural information and viable drug-like leads. Using the latest in Structural biology and drug discovery techniques, we intend to generate novel chemical compounds that have potent anti–bacterial features for therapeutics targeting TB and other pathogenic bacteria.
arthur roberts

Arthur Roberts
Assistant Professor

I am interested in studying the interaction of drugs with multiple-drug resistance transporters and drug-metabolizing UDP-glucuronosyltransferases.  These proteins play major roles in cancer resistance, in neurological diseases (e.g. Alzheimer’s disease and Parkinson’s) and in mitigating the effects of environmental pollutants.  Using human proteins isolated from genetically engineered yeast or bacteria, one goal is to develop structural biology tools to rapidly and accurately predict the effects of drugs and toxins before they end up in people.  These tools will allow us to design next generation drugs that are more effective and have fewer side effects than current medications.  Another goal is to develop advanced NMR and computational methods to probe the effects of drugs and toxins in whole cells.  These techniques will allow us to probe the complex interplay between transporters, receptors and enzymes during drug and metabolite processing.  In addition to these research goals, I am developing creative and novel teaching methods to train students of different skill levels in my laboratory.  Achieving these research and teaching goals will not only advance medicine and improve drug therapies, but will prepare students well for industry or academic careers in the 21stcentury.

houjian cai

Houjian Cai
Assistant Professor

Prostate cancer is the second leading cause of cancer-related deaths in men in North America. Several funding agents have invested in the study of this disease. The pathological stages of prostate cancer begin with abnormal epithelial proliferation and prostatic intraepithelial neoplasia, with progression to invasive carcinoma, and eventually metastatic disease, the stage in which most patients die.

In our research, we use a mouse model to recapitulate the progression of invasive stages of prostate cancer in vivo to understand the genesis of the disease, and to find drugs to target cancer cells in this stage. Our study takes advantage of adult stem cells existing in mouse prostate tissue. Provided with a suitable microenvironment, the stem cells will regenerate into prostate tissue. This regeneration system allows us to evaluate the ability of epithelial stem and progenitor cells to form normal prostate tissue, but also to assess the tumorigenic potential of oncogenes. In assistance with the capability of the isolation of adult stem cells and lentiviral transduction, my lab has successfully used the system to evaluate one single oncogene or the synergy of multiple oncogenes in prostate epithelium and the paracrine factors in the mesenchymal compartment in promoting prostate tumorigenesis.

Our on-going studies focus on the crosstalk of oncogenic signaling pathways, which will help us understand the initiation of invasive prostate cancer in vivo and identify drugs to target prostate tumorigenesis using genetic approaches and in complement small molecule inhibitors. The long term goal of my lab is to interrogate the molecular mechanisms underlying advanced prostate carcinoma and provide the scientific rationale for using small molecule inhibitors to suppress aggressive prostate cancer.

yujun george zheng

Yujun George Zheng
Associate Professor

Medicinal Chemistry, Drug Discovery, Organic Synthesis, Chemical Biology, Bioorganic Chemistry, Epigenetics, Histone Modification, Molecular Biology, Biochemistry, Enzymology, Biophysics, and Bioinformatics.

Dr. Zheng’s research lab works on the forefront area of chemistry, biology and medicine. In the post-genomic research era, there has been a great shift in focus from simply collecting and archiving genomic data to dissecting and interpreting complex genomic/proteomic functions and networks. We are particularly interested in addressing critical problems and challenges in the rapidly evolving field of epigenetics that usually describes gene expression profile changes that are irrelevant to genomic sequence. Mounting data show that epigenetic processes play pivotal roles in transforming normal cells into malignant tumors and in various other pathologic conditions. Abnormality in epigenetic landscape presents characteristic biomarkers for disease diagnosis. The importance of epigenetic regulation in disease initiation and evolvement also signifies a new flow of challenges and opportunities to disease research and pharmaceutical discovery. Therefore, identifying key chromatin regulatory factors such as histone modifying enzymes and chromatin remodeling complexes, understanding their activity, specificity and functional roles, and inventing potent and selective drug compounds embody demanding needs in today’s biology and pharmaceutical research. Our lab is innovating and applying advanced chemical and biological strategies, tools and agents to elucidate functions of epigenetic enzymes in disease mechanism and meanwhile provide new diagnostic and therapeutic regimens. The lab adopts an interdisciplinary approach, spanning and integrating organic chemistry, medicinal chemistry, bioorganic chemistry, molecular biology, biochemistry, enzymology, cellular biology, biophysics and bioinformatics, and a wide range of techniques are employed.

Current active research areas include: (1) development of potent and selective epigenetic therapies, (2) design of chemical probes to understand protein acetylation and novel lysine acylation, and (3) mechanistic and functional study of protein arginine methylation.