Thomas R. Hoye, Principal Investigator

Design of Peptidomimetics as Anti-HIV and Antiangiogenic Antitumor Agents; Computation of Proton and Carbon NMR Chemical Shifts

Molecular modeling is a powerful tool for guiding the design of new targets for organic synthesis. Identification of novel biologically active agents is one valuable application.

This research group engaged in designing non-peptidic analogs based on known, active peptidic lead compounds. Representative examples of projects where such approaches benefit this research are:

• The design of a new class of enzyme inhibitors as potential anti-HIV (human immunodeficiency virus) agents. These were based upon structural information available from crystallographic studies of complexes between various peptidic agents (cyclosporin A and p55gag fragments) and human cyclophilin A. It is clear that the latter, host-cell protein must be recruited into new HIV virions to render the latter infective.
• The design of new antiangiogenic antitumor agents. These were based upon knowledge of a requirement for certain side chain substituent nature and relative orientation in known antiangiogenic polypeptidic agents.

Design of structures built on scaffolds displaying these residues in similar fashion were guided by modeling studies.

A new project initiated by this team uses nuclear magnetic resonance (NMR) spectroscopy to determine the three-dimensional structure (i.e., stereostructure, which encompasses the relative and absolute configurations of the molecule) of organic compounds, including the important subset of natural (and unnatural) products having useful biological activities. The precise sterostructure imparts the biological function to such compounds. Thus, methods for unambiguously determining complete stereochemical structures are of considerable value. The researchers have begun to develop new methodologies that involve the comparison of computed with experimental spectroscopic parameters. The two principal types of information that are at the very core of nearly all NMR spectroscopic analyses are chemical shifts (δ) and coupling constants (J). In principle, these values can be computed for an entire family of possible stereoisomers and then compared with the experimental values to allow for deduction and assignment of the correct structure. The hypothesis is that comparison of computer chemical shifts for each member of a family of possible stereoisomers with the experimental chemical shifts for a single stereoisomer for which the relative configuration is not yet known, will allow the configuration of that compound to be deduced with confidence.

Research Group

Ziyad Al-Rashid, Graduate Student Researcher
Andrew Aspaas, Graduate Student Researcher
Michael Danielson, Graduate Student Researcher
Brian Eklov, Graduate Student Researcher
Carolee Flader, Research Associate
Yan He, Graduate Student Researcher
Min Hu, Graduate Student Researcher
Shengxiang Ji, Graduate Student Researcher
Jim Kabrhel, Graduate Student Researcher
Hollie Lewis, Graduate Student Researcher
Troy Ryba, Graduate Student Researcher
Manomi Tennakoon, Graduate Student Researcher
Jizhou Wang, Graduate Student Researcher
Peng Zhao, Graduate Student Researcher