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Research Abstracts Online
January 2008 - March 2009

University of Minnesota Twin Cities
College of Pharmacy
Department of Medicinal Chemistry

PI: Elizabeth A. Amin, Associate Fellow

Modeling and Targeting Zinc Metalloproteins

This group used MSI resources for two projects during this period. The first research area is a study of anthrax toxin lethal factor inhibition. Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis, and has been used as a biological warfare and terrorism agent, with high mortality rates upon exposure in inhalation form. Inside the host, anthrax spores secrete a tripartite exotoxin comprising the lethal factor (LF), edema factor (EF) and protective antigen (PA), encoded by the pXO1 plasmid. LF is most critical for pathogenesis, as it cleaves members of the MAPKK family, interferes with signaling pathways that recruit immune cells during the inflammatory response, and directly enables B. anthracis to evade host immunological mechanisms. The only treatment currently available against anthrax is antibiotics, but high levels of LF can remain in the system for days after B. anthracis has been cleared by antibiotics, and can produce fatal residual toxemia in the absence of viable bacteria. Currently there are few, if any, effective therapeutic options available to counteract LF-mediated toxicity at any stage of anthrax infection. By means of a novel computational and experimental strategy incorporating virtual screening, 3D-QSAR, pharmacophore mapping, topomeric searching, library generation, lead optimization and in vitro high-throughput screening, the Amin laboratory has identified a series of promising lead compounds that demonstrate favorable binding affinity to the LF active site. They are further optimizing these compounds toward therapeutics that can aid persons who have been, or suspect they may have been, exposed to anthrax spores in an emergency situation.

The second research area concerns new strategies for modeling zinc bio- and nanocenters. Molecular modeling of physiologically critical zinc metalloproteins has been limited by the lack of reliable force-field parameters, a roadblock further complicated by the fact that zinc often functions catalytically in these enzymes and undergoes unusual coordination changes at transition states. The Amin laboratory is working toward the creation of new computational parameters for biologically significant zinc-binding proteins, and they plan to implement these parameters as part of a novel neglect of diatomic differential overlap (NDDO) method for use in metalloprotein and nanostructure simulations. They are also investigating a new scheme for modeling reactive potential energy surfaces in large metal-bearing molecules, where the computational requirements scale linearly with system size and no diagonalization or iterations are required, rendering these schemes well suited to simulating large systems. They plan to optimize the functional forms and parameters of this new model as part of a new Zn macromolecule modeling system, to be tested and validated by means of experimental data pertaining to a series of pertinent zinc-binding proteins such as the cytidine deaminases, and medically important zinc metalloenzymes such as the anthrax toxin lethal factor.

Group Members

Ting-Lan Chiu, Research Associate
Bryant Gay, Graduate Student
Christopher P. Glenski, Undergraduate Student
An Na Kim, Graduate Student
Abhrajeet V. Roy, Supercomputing Institute Undergraduate Intern
Anastassia Sorkin, Research Associate
Richard L. Wood, Research Associate
Xia Zhang, Graduate Student