Our research group is interested in the rational X-ray structure-based drug design (SBDD) and synthesis of small molecular weight chemical modulators of enzymes, protein-protein, and protein-carbohydrate interactions. These chemical biology tools are specifically designed to bind protein targets and are utilized for studying both the molecular recognition of protein ligands and corresponding disease mechanisms. Furthermore, our group has extensive industrial experience and expertise in drug discovery. The initial tool compounds identified either by X-ray structure-based de novo ligand design or high-throughput screening (HTS) serve as lead molecules for further medicinal chemistry optimization and development into innovative therapeutics mainly for the treatment of cancer and infectious disease.
Our multifaceted approach includes the development of novel peptide mimics, carbohydrate mimics, and heterocyclic small molecule inhibitors (or antagonists) of protein targets. The protein targets of interest are initially chosen and prioritized by evaluating known experimental evidence of disease association (e.g. overexpression or mutation) of the target and/or relevant biological pathway(s). The majority of targets we are interested in function at a much higher level and in some cases in an uncontrolled or unregulated manner in the pathological state relative to the normal healthy state. Therefore, our goal is to block the activity of the malfunctioning overactive protein by designing small molecular weight ligands which specifically bind to and inhibit the protein’s function and downstream biological effect(s).
While medicinal chemistry and synthetic organic chemistry are central to our research for the discovery and optimization of these powerful chemical tools and potential therapeutics, chemical biology and drug discovery are clearly multidisciplinary fields. To this end, we collaborate closely with principal investigators in bioinformatics, biochemistry, cell biology, computational chemistry, structural biology, pharmacology, and clinical departments in order to elucidate, assess, and further improve the biological effects of these innovative chemical research tools.
We are currently focused on three main projects: 1) protease inhibitors of growth factor activation for the prevention and treatment of metastatic cancer; 2) protein-protein interaction (PPI) antagonists of DNA damage repair proteins for the treatment of platinum-resistant cancer; 3) carbohydrate-protein interaction (CPI) antagonists of bacterial virulence factors for the treatment of urinary tract infections (UTI).