Computational Models for Predicting the Binding Affinities of Ligands for the Wild-Type Androgen Receptor and a Mutated Variant Associated with Human Prostate Cancer

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Abstract
In the present study, values of the binding energy (BE) were calculated for the rat androgen receptor on a data set of 25 steroidal and nonsteroidal compounds for which published values of the observed binding affinity (Ki) are available. A correlation between BE and pKi was evident (r2 = 0.50) for the entire data set and became more pronounced when the steroids and nonsteroids were plotted separately (r2 ≅ 0.76). Including BE as an additional descriptor to supplement the default steric−electrostatic descriptors in comparative molecular field analysis dramatically improved the predictive ability of the resulting three-dimensional quantitative structure−activity relationship models. We also demonstrate that the observed loss in ligand specificity between the wild-type (wt) AR and the T877A mutant AR associated with androgen-independent prostate cancer is reflected in decreased BE values (i.e., higher binding affinity) for the antiandrogen pharmaceutical hydroxyflutamide and for several nonandrogenic endogenous steroids, most notably cortisol, corticosterone, 17β-estradiol, progesterone, and 17α-hydroxyprogesterone.

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