UMBC Chemistry and Biochemistry basic

X-ray diffraction pattern

SAXS data collection and processing

Nitric oxide (NO) is a small, transient, diffusible molecule that plays a dual role in many physiological processes as a biological messenger and a cytotoxic agent against tumor cells, viruses and pathogens. NO availability is solely regulated at the synthesis level by three nitric oxide synthase (NOS) enzymes. Both over- and under-production of NO by the NOS isoforms are linked to various human pathologies, including immune-type diabetes, stroke, inflammatory bowel disease, rheumatoid arthritis, hypertension, arteriosclerosis, cancer, and infection susceptibility. A strategy for treating these disorders includes the development of highly selective inhibitors that target iNOS and nNOS, but not eNOS. Structural studies have guided the development of potent and selective iNOS and nNOS inhibitors, yet preclinical studies have demonstrated significant toxicity limiting their testing in a clinical environment.

An alternate therapeutic strategy to modulate NO-mediated events is the development of small molecules that target the direct mediators of NO signal transduction. These mediators are often enzymes, which are directly modified by NO. NO modifies proteins by binding to metals and cysteine thiol groups (S-nitrosation) to modulate enzyme activity, localization, and association with other proteins.

Research in this lab will address key questions regarding the mechanisms by which nitrogen oxide affect catalytic activity and dynamic association with regulatory proteins. Combined biochemical (protein characterization, activity assay, protein modification), biophysical (FRET, DXMS) and structural analyses (x-ray crystallography and small-angle x-ray scattering) to elucidate the structural basis of nitrogen oxide-induced conformational changes of clinically relevant targets will provide a powerful molecular framework for the design of novel small molecules compounds for the treatment of hypertension, heart failure, atherosclerosis, diabetes, metabolic syndrome, and vascular disorders (Alzheimer’s disease) with neurodegenerative consequences.