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

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Introduction 
The androgen receptor (AR) is a steroid receptor transcriptional factor for testosterone and 
dihydrotestosterone consisting of four main domains, the DNA binding domain (DBD), the ligand 
binding domain (LBD), the hinge region, and the N-terminal domain
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(Figure 1).
AR activity is upregulated in a variety of different cancer types. In breast cancer, approximately 
60-80% of patients showed this up-regulation
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and in pancreatic cancer, the survival rates of those 
found to have up-regulation in the AR pathway was almost 0% for one year
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. Most notable 
however is the AR’s role in prostate cancer, where approximately 50% of the patients studied 
showed up-regulation or mutations in this pathway
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. Prostate cancer is the most common cancer 
in men and the second leading cause of death for any form of cancer
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. After progression of the 
cancer, the tumor enters a new phase in which the prostate cells employ multiple self-defense 
mechanisms that allow it to survive in a low androgen environment
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. Evidence now suggests that 
both residual androgens and the AR play a key role to the progression of the disease to these 
stages
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. The human AR is a common target for treatment of prostate cancer growth. In the 1940s, 
Charles Huggins was the first to discover that androgen ablation therapy was a successful treatment 
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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for patients with metastatic prostate cancer
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. This was based off increasing evidence that the AR 
activity persists even in patients with the castration-resistant form of prostate cancer, leading to 
the belief that the AR is a valid drug target for all stages of the disease
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. Treatments of prostate 
cancer focusing on the AR have become common. An emerging area of focus is the usage of 
curcumin and various analogs to chemically target the AR in prostate cancer patients. The natural 
product curcumin and its analogs have been found to show potent antioxidant activity
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, anti-
inflammatory activity
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, cytotoxicity against tumor cells
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, and anti-tumor-promoting 
activities
13,14
. The multitude of beneficial activities of curcumin and its pharmacologically safe 
profile, together with its well-known limitations with respect to bioavailability, lead to many 
structure activity relationship (SAR) studies using 
de novo
synthesized analogs
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. A special group 
of synthetic analogs of curcumin are the diarylpentanoids that seem to show an elevated anti-tumor 
and oxidant effect in several cell models
16,17
. In 2006, Weber et al introduced a series of 
diarylpentanoid analogs with inhibitory effect for the nuclear factor kappa B (NFκB)
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. Among 
these compounds was curcumin analog ca27.
ca27 was studied further and found to down-regulate the AR protein expression in human 
prostate cancer cell models, including LNCaP and LAPC4, as well as led to the rapid induction of 
reactive oxygen species (ROS)
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(see below). These findings marked ca27 as a potential lead 
compound for the development of therapeutic compounds for prostate cancer. However, these 
studies did not identify the exact mechanism of action (MOA) of ca27. The latter remains to date 
a substantial gap of knowledge and warrants further investigations, which is the very essence of 
this research.

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