DEDICATION
This thesis is in dedication to my parents, James and Cherie Guillow, for always pushing me to be
the best I can be and to strive for greatness.
ACKNOWLEDGEMENTS
I would like to thank Dr. Bisoffi for introducing me to this subject material and for encouraging
me to pursue this research. I would like to thank Dr. Verkhivker for contributing his expertise on
the subject matter. I would also like to thank Dr. Owens for his guidance throughout this process
as well as Dr. Orry for taking the time out of his busy schedule
to contribute his wealth of
knowledge on the methodology to this project. Finally, I would like to thank Dr. El-Askary and
the rest of the CADS department and Chapman University for their guidance and support.
ABSTRACT
Computational Molecular Docking Models and Design of Diarylpentanoids for the
Androgen Receptor
by Jarett A. Guillow
The androgen receptor (AR) is a member of the nuclear receptor protein family that, upon binding
to its natural ligand dihydrotestosterone (DHT) in the cytoplasm, translocates to the nucleus and
exerts nuclear transcription factor activity to drive gene expression
related to normal prostate
development. AR signaling becomes overactive during the development and progression of
prostate cancer through different mechanisms, including over-expression and mutation of the AR.
Therefore, the AR is a prominent molecular target in the clinical management of prostate cancer.
However, all therapeutic modalities targeting the AR, including androgen ablation therapy and AR
block suffer from transient efficacy and invariably lead towards resistance and more aggressive,
metastatic disease. Therefore, it is imperative to develop new therapeutic approaches. ca27 is a
diarylpentanoid organic small molecule analog of the natural product curcumin that was previously
shown to down-regulate the expression of the AR and to induce prostate cancer cell death. While
its mechanism of action remains unknown, we hypothesized a potential physical interaction with
the AR, leading to its degradation. In this research, we analyzed the AR in the DBD and LBD both
in binding pockets and in the entire domain. The results indicate negligible binding to the DBD
and positive binding in both binding models of the LBD. Further analysis of the models indicates
the presence of a new binding pocket, hereby referred to as the ca27 binding pocket, in the LBD
where ca27 and its various analogs bind in non-competition to the natural DHT ligand. These
results were developed in MolSoft ICM Pro and further verified by AutoDock through 1-Click
Docking. Further research into designing new ligands was performed however the results were
inconclusive and needs further study.
Keywords:
Androgen
Receptor, dihydrotestosterone,
prostate cancer, ca27, curcumin,
diarylpentanoid, MolSoft, AutoDock,
ligand binding domain, DNA binding domain.
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