| Summary: | The three dimensional structure of both a ligand and its cognate receptor
are required for the success of structure-assisted drug design. This thesis reports
the crystal structure of hectochlorin, a small, bioactive molecule, and the steps
toward determining the crystal structure of an RNA molecule that is an attractive
target for drug design.
The absolute structure of hectochlorin, a cytotoxic, secondary metabolite
isolated from Lyngbya majuscula, is reported herein. Specifically, the absolute
configuration of hectochlorin, as determined by x-ray crystallography, is
reported as 6S, 7S, 10S, 31S. Marine natural products are interesting as a source
of novel chemical compounds that are potentially valuable as therapeutic agents,
or have industrial applications. The absolute structure provides a model that
serves as a starting point for rational drug design synthesis.
In a second study, results are reported from attempts to crystallize a
biologically important RNA structure, the trans-acting response element, (TAR),
for the determination of its structure by x-ray diffraction, and ultimately,
providing an initial model for structure-assisted drug design targeted against
HIV. Crystals, of biologically relevant TAR sequences, greater that 0.1 x 0.1 x 0.1
mm�� in size, both in the presence and absence of a cognate ligand analogue,
have been obtained. These crystals have been shown to be of poor diffraction
quality, but the initial crystallization conditions provide a starting point for
optimization that may yield higher quality crystals. === Graduation date: 2001
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