Antagonists of androgen receptor (AR) are used in the clinics for treating prostate cancer. To date, no experimental AR structure in antagonistic form is available, which greatly complicates discovery of new AR antagonists. Modeling of the antagonistic structure of AR is very challenging due to lack of reasonably homologous templates, although there are hundreds of structures that are similar to AR in 3D. We developed a structural bioinformatics tool that helped us identify the best templates. The models we built are based on antagonist-bound structures of estrogen and glucocorticoid receptors. Due to very low homology to the templates we used a combination of sequence-independent 3D superposition procedure for the 3D-conserved part of the protein followed by modeling based on manual alignment for the H12 helix. The models were validated by docking known antagonists. In addition, we synthesized a library of 3-hydroxy-2,3-dihydropyridones and tested their activity as antiandrogens in the human prostate cancer cell lines LNCaP. The design resulted in the identification of a potent compound, whose binding and cell activity is comparable to approved drug MDV3100. The model is qualitatively consistent with the SAR observed. Moreover, the enrichment plot shows that screening with the model performs significantly

Design of antiandrogens: Challenge of receptor modeling

246th National Meeting (2013)

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