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LIST OF FIGURES
Page
Figure 1:
Protein / gene organization of the androgen receptor (AR). The AR gene is located on
the X chromosome and is 919 base pairs long. It consists of 8 exons that translates into a protein
of 110 kDa. There are 4 distinctive domains: The N-terminal domain (NTD), which contains
typical poly-glutamine stretches, a DNA binding domain (DBD), a hinge region, and a C-terminal
ligand binding domain (LBD).
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Figure 2:
Signaling pathway of the androgen receptor (AR). Testosterone (T) bound to sex
hormone binding protein (SHB) enters the cell and is converted by 5α-reductase to
dihydrotestosterone (DHT). DHT dislocates heat shock binding protein 90 (HSP90) from the AR
and binds it with high affinity. AR dimerizes and becomes phosphorylated (P), then translocates
to the nucleus where it recognizes promoter regions containing androgen responsive elements.
Upon recruiting several Co-regulators (Co-Reg) and the general transcription apparatus (GTA),
it induces the transcription of pro-proliferative and pro-survival genes, as well as the biomarker
prostate specific antigen (PSA).
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Figure 3:
The diarylpentanoid ca27 down-regulates the expression of the mutated AR in LNCaP
human prostate cancer cells at low micromolecular concentrations. Protein expression is shown
by Western blot and quantification normalized to the housekeeping gene β-actin
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.
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Figure 4:
The diarylpentanoid ca27 and its structural analogs CA58 (meta-positioned hydroxyl
[OH] groups), CA51 (para-positioned OH groups), ca27 MA- (lacking the Michael acceptors),
and ca27 OH- (lacking the OH groups). Right bottom: The natural product curcumin with its
functional groups.
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Figure 5:
All different ligands bonded to the LBD of the AR. A) depicts ca27, B) depicts ca58, C)
depicts ca51, D) depicts ca27 without hydroxyl groups, E) depicts ca27 with the Michael
acceptors, and F) depicts the negative control docetaxel.
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Figure 6: A graphical rep of the scores of the different ligands bonded to the human AR LBD with
corresponding
scores with a positive control,DHT, and a negative control of docetaxel ... 9
Figure 7:
All different ligands bonded to the DBD of the AR. A) depicts ca27, B) depicts ca58, C)
depicts ca51, D) depicts CA27 without hydroxyl groups, E) depicts CA27 with the Michael
acceptors, and F) depicts the negative control docetaxel.
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Figure 8: A graphical rep of the scores of the different ligands bonded to the human AR DBD with
corresponding scores and a positive control of PP and a negative control of docetaxel ... 10
Figure 9: A comparison graph of binding scores in the DBD (red) and the LBD (blue). . 11
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Figure 10:
Three-dimensional structure of the androgen receptor ligand binding domain (LBD)
and DNA binding domain (DBD). The arrow in LBD denotes the natural ligand
dihydrotestosterone (DHT). The DNA is indicated below the DBD.
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Figure 11: DHT crystal structure and the DHT ligand bound to the DHT binding pocket in the
LBD viewed in MolSoft .................................................................................................... 24
Figure 12: Docking Results for the various ligands in the LBD centered at the DHT binding pocket.
A is DHT. B is ca27. C is ca51. D is ca58. E is ca27 without MA. F is ca27 with OH groups. G
is Docetaxel. F is MG132. ................................................................................................ 26
Figure 13: Docking Results for the various ligands in general LBD without specifiying a binding
pocket. A is DHT. B is ca27. C is ca51. D is ca58. E is ca27 without MA. F is ca27 with OH
groups. G is Docetaxel. F is MG132. .............................................................................. 28
Figure 14: The new binding pocket (ca27 binding pocket) compared in location, surface area, and
volume to the DHT binding pocket. .................................................................................. 29
Figure 15: Outline of the residues surrounding the new ca27 binding
pocket with the highest
probability of interacting with bound ligands. .................................................................. 29
Figure 16: Docking Results for the various ligands in DBD centered at the binding pocket. A is
PP. B is ca27. C is ca51. D is ca58. E is ca27 without MA. F is ca27 with OH groups. G is
Docetaxel. F is MG132. .................................................................................................... 32
Figure 17: Docking Results for the various ligands in the general DBD without specifiying a
binding site. A is PP. B is ca27. C is ca51. D is ca58. E is ca27 without MA. F is ca27 with OH
groups. G is Docetaxel. F is MG132. .............................................................................. 33
Figure 18: Docking Results for the various ligands in the LBD centered at the DHT binding pocket
by 1-Click Docking. A is DHT. B is ca27. C is ca51. D is ca58. E is ca27 without MA. F is ca27
with OH groups. ................................................................................................................ 35
Figure 19: Docking Results for the various ligands in the LBD centered at the ca27 binding pocket
by 1-Click Docking. A is DHT. B is ca27. C is ca51. D is ca58. E is ca27 without MA. F is ca27
with OH groups. ................................................................................................................ 37
Figure 20: The outputted ligand from AutoLigand (left) and the binding of this new ligand to the
AR LBD in MolSoft .......................................................................................................... 38
Figure 21: The new ligand produced by AutoLigand bound in 1-Click Docking centered at the
DHT binding pocket (left) and the ca27 binding pocket (right) ........................................ 39