Computational Molecular Docking Models and Design of Diarylpentanoids for the Androgen Receptor

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Previous MolSoft ICM Results from Undergraduate Senior Capstone 
Molecular docking modeling of ca27 and its analogs has already been attempted as a senior 
undergraduate biochemistry capstone project. During this research, ca27 and multiple different 
analogs were bonded to both the LBD and the DBD of the AR and their respective binding 
affinities were compared to the natural ligands to determine the favorability of the analogs.

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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.

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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.