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

2.5
 
Flexibility in the DBD and LBD 
One main concern is the comparison of the rigidity versus flexibility of the receptor model. It is 
known that calculations based off a single rigid receptor are inadequate to reproduce the natural 
complex geometry of the complex in more than 50% of reported cases
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. This leads to a need to 
introduce receptor flexibility in both the DBD and the LBD of the model in order to account for 
the conformational changes that occur during ligand binding. In order to introduce said flexibility, 
the most novel and optimal technique is to represent the receptor flexibility itself as a 4
th
discrete 
dimension of the molecular conformational space by using multiple 3D grids comprised of 

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superimposed conformers merged into a single 4D object
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. In order to accomplish this goal, there 
must be receptor and ligand preparations completed, followed by the docking simulations and the 
energy evaluations, all of which can be completed and was completed using MolSoft ICM 
software. 

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 3
 
Hypothesis 
1.
We hypothesize that ca27 and its analogs bind directly to the DBD and the LBD of the 
AR, which causes a conformational change in the structure of the AR, thereby inducing 
its degradation, which manifests itself as the observed down-regulation of its expression. 
2.
We further hypothesize that the presence/absence and the position of the hydroxyl groups 
on the aromatic rings will substantially influence the binding in both domains. Similarly, 
we hypothesize that the presence/absence of the alpha-beta unsaturated carbon bonds 
(also known as Michael acceptors) will also be essential in determining the binding of 
these organic small molecules to the AR. 
3.
We finally hypothesize that a detailed knowledge of the binding between ca27 and the 
AR leads to the identification of new compounds with increased AR binding affinity 

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