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Darrell R. Davis

Professor and Interim Chair of Medicinal Chemistry and Professor of Biochemistry

B.S. University of Puget Sound

Ph.D. University of Utah

Research

References

darrell.davis@hsc.utah.edu

Darrell Davis' Lab Page

Darrell Davis' PubMed Literature Search

Research

My laboratory is involved in the study of nucleic acid and protein structure using high-field NMR spectroscopy. We have recently developed a structure-based drug design program focused on discovering and optimizing small molecules that interact with biomedically relevant RNA targets. NMR spectroscopy is uniquely suited to solving the 3D structures of RNA domains in complex with inhibitor molecules, and NMR also is a unique tool for identifying lead compounds that only interact weakly with macromolecules. The University of Utah has an outstanding biomolecular NMR facility with 500, and 600 MHz instruments locally, and access to 800 and 900 MHz instruments at the University of Colorado.
Hepatitis C virus (HCV) infection is a major cause of liver cancer in the US and liver disease associated with HCV accounts for the majority of liver transplants. In the developing world, a high percentage of HIV patients are also co-infected with HCV, presenting a particularly challenging health problem. The 5’ untranslated region of the HCV RNA genome contains a large structured domain that serves as an IRES (internal ribosme entry site) that enables 5’ cap independent RNA translation. The IRES of HCV is an attractive therapeutic target since it is crucial for HCV replication. The RNA has a well-defined structure, raising the possibility for developing targeted therapeutics against HCV.

Our laboratory has solved the structure of a functionally important domain of the HCV IRES RNA in complex with an inhibitor of viral replication. Current research in the laboratory involves using NMR to screen for additional inhibitors that bind this target. We are also using NMR for a structure-based drug design initiative aimed at developing next-generation inhibitors with improved potency. The structure based design project is multi-disciplinary, with a computational chemistry component in collaboration with the Cheatham laboratory, and a synthetic chemistry initiative in collaboration with the Rainier laboratory.

(Left) Superposition of NMR structures for a domain of the hepatitis C virus internal ribosomal entry site RNA complexed with an inhibitor. (Right) Correlation of experimental CH residual dipolar coupling NMR restraints. Open circles are calculated values of the free RNA plotted against the experimental RDC values of the complex, showing that the free RNA does not fit the experimental data, while closed circles are for the inhibited structure indicating a good fit with experiment.

References