Computer modeling including graphics and energy calculations were employed for the first time to examine the stereochemical fit of antiandrogens into double-stranded DNA. In this study, we assessed the relative fit of antiandrogens in the cavity between base pairs known to accommodate androgens. When compared to testosterone which was given a normalized value of 100%, the antiandrogens manifested the following order of fit: RU23908 (88%) > hydroxyflutamide (71%) > cyproterone acetate (41%). A correlation was observed between the relative fit of the antiandrogens and reported agonistic properties as assessed by the ability to increase nuclear androgen receptor levels in the rat ventral prostate. These findings may be useful in the design and development of androgen antagonists without agonistic activity.
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