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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.
The first binding
attempt was done in the LBD, which was hypothesized to be the favorable
binding domain based off previous biochemical assays and studies. In this experiment, the LBD
was defined by the pre-existing ligand DHT by examining possible sources of interactions between
the receptor and the ligand. DHT was then removed from the complex and was in turn replaced
with ca27 and its various analogs. The LBD showed favorable binding for all the different analogs
with a variety of different affinities with the positive control of DHT and the negative control of
docetaxel indicating normalized scenarios. Figure 5 shows the different ligands bounded to the
LBD (inside the blue pockets for each image) and figure 6 depicts
a quantitative graph of the
favorability of each ligand bonded to the receptor where the more negative score is favorable. The
quantitative graph depicts ca27 to have favorable binding, however, the favorability is not as high
as the natural ligand DHT that would inhibit the binding. However, one of the analogs, ca58,
showed favorable binding near comparable to the natural ligand DHT. This leads ca58 to be the
primary molecule of interest despite its free energy being closer to zero than DHT.
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Figure 6:
A graphical representation of the scores of the different ligands bonded to the
human AR LBD with corresponding scores with a positive control of
DHT and a negative
control of docetaxel
The second binding attempt was completed in respects to the DBD. In this domain, because
of the transcriptional function of the DBD, it has no natural ligand. However, pyrvinium pamoate
(PP) has been shown to have a strong binding affinity to the DBD and was used as the positive
control. PP was exposed to the AR and all possible interactions between the two were mapped
and used to define the DBD. The DBD showed similar results
as the LBD in regard to the
favorability of the binding for the different ligands. Figure 7 shows the different ligands bounded
to the DBD (inside the blue pockets of each image with an arrow indicating their locations). Figure
8 shows a graphical representation of the favorability of each of the ligands bonded to the AR
DNA interaction sites in which the more negative the score represents the more favorable binding
ligand.