RESEARCH

AREAS OF FOCUS

  • STRUCTURE-BASED DRUG DESIGN: Structure and Function of Enzymes in the Pyrimidine Biosynthesis Pathway


  • ENERGY STORAGE: Structure and Function of Aldehyde Decarbonylase

  • NOVEL ANTIBIOTICS: Structure and Function of mprF


  • NATURAL PRODUCTS: Small molecule structure determination using ultrasmall samples, powder diffraction, or MOF materials


  • NEURODEGENERATIVE DISEASES: Structure and function of kynurenine 3-monooxygenase


STRUCTURE-BASED DRUG DISCOVERY

We are studying the enzyme dihydroorotase which is a gene product of the essential enzyme pyrC in the pyrimidine biosynthesis pathway of B. anthracis, M. tuberculosis, P. falciparem, and S. aureus. Several structures have been determined for the E. coli organism, among others, but we are focusing on these two Gram-negative and two Gram-positive organisms, as a general approach in the development of broad-spectrum antibiotics. We are using high-throughput compound library screening, in-silico virtual library screening, computational docking and molecular dynamics to aid in drug discovery.


ENERGY STORAGE AND CATALYSIS

Alcohol decarbonylase is found in a number of microbes and plants, and converts aldehydes to alkanes with cobalt porphyrin in the active site. There are no structural studies of this enzyme, and it would be useful in generating alkanes for diesel oil production. It is also an interesting target for structural manipulation (directed evolution) to study the link between enzyme structure and function, and improve catalytic efficiency and protein stability.


NOVEL ANTIBIOTICS

The enzyme mprF is required for lysinylation of phospholipids in integral membranes, and generally confers resistance to cationic antimicrobial peptides (CAMPs). The mprF gene is an essential enzyme in several organisms, and we are determining the structure as a prelude towards drug discovery and the development of a new class of antibiotics. This system affords a unique opportunity to investigate the inate immune response from a number of pathogenic bacteria.


NATURAL PRODUCTS

A number of methods are being explored to push the limits of small molecule crystallography. Our approach include advances in the nanoliter crystallization of small molecules using novel crystallization additives, high-throughput screening, and intense synchrotron x-ray sources and large sensitive photon detectors, in addition to the development of powder diffraction on very small samples, or compound co-crystallization with simple metal-organic frameworks . X-ray diffraction remains the definitive choice when assigning absolute stereochemistry to unique chemical scaffolds. These studies augment the extraction of novel compounds from plant and marine sources and is part of unique pharmacognosy studies at UIC.