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

 4
 
Specific Aims 
1.
To determine the binding affinity of ca27 and its analogs to the LBD and the DBD of the 
AR using a computational modelling approach.
•
This will be accomplished using the MolSoft docking/modelling software, which will 
determine the geometric and chemical strain for ca27, and its analogs based of the free 
energy present in the model (further described in section 6) in order to conclude which 
features the best physical binding. The results will be corroborated with another, 
independent software, AutoDock. These studies are accompanied by biochemical 
experimental approaches (outside of this proposal) that are ongoing in Dr. Bisoffi’s 
laboratory. 
2.
To design 2 new organic small molecule(s) with increased binding affinity. One of 
which will be of the same structure as ca27 including the polyphenol rings and the other 
will be of any structure simply optimizing the binding affinities.
•
This will be accomplished by using the results from specific aim 1. In particular, details 
on structural pharmacophores with elevated binding affinity will be utilized to design 
de 
novo
novel molecular organic structures. This information will be included into 
AutoDock and MolSoft ICM to then optimize the interactions and output the most 
favorable docking model using guidelines specified by the user. These structures will be 
synthesized by collaborator and organic chemist, Dr. Justin O’Neill (Schmid College of 
Science and Technology, Chapman University).

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18 
 5
 
Significance/Impact 
5.1
 
Short-Term Significance/Impact 
This investigation contributes to the current trend to query the binding capacity of potential 
modulators, regulators, and inhibitors of nuclear receptors OUTSIDE of the known binding 
pockets. This is also an ongoing trend for the AR, as summarized in Elshan et al (2018)
27
. We 
expect our research to contribute to this trend and to identify novel binding sites on two domains 
of a rather well-known protein. We expect that this will lead to the identification of structural 
groups of organic small molecules that may be the source for the development of novel active 
pharmacophores to be tested for their ability to down-regulate AR expression. Hence, the present 
work will foster several experimental research avenues, including the chemical synthesis of novel 
molecules and their testing in biophysical and biochemical 
in vitro
assays to complement and/or 
corroborate the results found herein. This in turn will warrant investigations of the effect of such 
novel compounds on AR expression in cell models, notably of human prostate cancer origin. In 
the long run, these results will ultimately have potential pre-clinical / clinical significance.