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

2.2
 
Computational Modeling of Curcumin and the AR 
Previous studies have used computational modeling to study a possible interaction between 
curcumin and curcumin analogs, and the AR. Of note, one study focused on contour maps 
generated by binding a variety of analogs of curcumin to the AR
21
. In this research, the 
investigators used three-dimensional quantitative structure activity relationships (SAR) software 
(3D-QSAR), SYBYL X 1.3 (Tripos Associates Inc., St. Louis, Missouri, USA, 2011), comparative 
molecular field analysis (CoMFA), and comparative similarity indices analysis (CoMSIA) to 
produce statistically significant results utilizing 40 different analogs of curcumin. After analysis 
using contour maps, the most active compound (compound 29) was used in further in-depth 
docking analysis to view the geometric interactions with the AR. After further studying compound 
29 and comparing the residual groups of each compound analyzed, a new group of 30 different 
analogs were derived that have the potential to be more active compounds than those initially 
studied, and their possible binding affinities and activity levels were hypothesized using their 
predicted pIC50 values
21
.
Another study focused on SAR studies of 44 different analogs of curcumin and then used SYBYL 
6.0 to further analyze target compounds classified to be a new class of antiandrogen agents
22
. Of 
these 44 compounds, the 5 determined to have antiandrogen effects were dimethylated curcumin 
(4), bis(methoxycarbonylmethyl) ether (20), ethoxycarbonylethyl (22), compound 23, and 1,3-
bis(3,4-dimethoyxphenyl)-1,3-propandione (39). The isolation of these 5 compounds led to an 
understanding through the SAR studies that bis(3,4-dimethoxyphenyl) moieties, a conjugated 
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7 
diketone, and an ethoxycarbonylethyl group at the C-4 position, play important roles in creating 
the antiandrogen effects. These findings may be important for future antiandrogen agents and will 
lead to further research and understanding as to what structures and substituents are pertinent to 
down regulating the expression of the AR
22
.
One last study of note utilized previous computational studies as well their own analysis in order 
to determined that a chemical compound with two bulky side chains would be effective in prostate 
cancer cell treatment and would down-regulate the expression of the AR
23
. The investigators 
found that they could obtain such compounds by incorporating two dietary agents, 
#
-ionone and 
curcumin, into one chemical entity. Eleven compounds were synthesized based off this concept 
and of them, one compound (compound 6) showed low micro molar cytotoxicity and potentially 
suppressed DHT-induced transactivation of the AR in prostate cancer cells. Through molecular 
docking modeling analysis, compound 6 was found to bind to the LBD of the AR at the hormone 
(DHT) binding pocket
23
. These results need to be corroborated with our research as this previous 
project was completed utilizing now outdated and possibly unreliable software.
Utilizing these previous studies as partial guides, a template approach was designed which guided 
this research, which is focused on the generation of new computational docking models of the 
potential binding of ca27 and its analogs to the AR.