The androgen receptor (AR) and estrogen receptor (ER) are steroid receptors and members of the nuclear receptor superfamily. Disruption of their function can lead to prostate cancer, androgen insensitivity syndrome and infertility for AR and breast cancer for ER. Testosterone and estradiol, the AR and ER endogenous ligands, bind in the steroid binding site of their respective receptor ligand binding domain (LBD). The AR and ER LBDs include two surface binding sites: activation function-2 (AF-2), where co-factors regulating transcription bind, and binding function-3 (BF-3), an allosteric regulatory site important for receptor activity. Studies showed compounds can bind in BF-3 and inhibit co-activator binding to AF-2. Additional studies showed that Endocrine Disrupting Chemicals (EDCs) can induce steroid release. We explore how EDCs bind to AR and ER disrupting their function. DDT and three DDT analogs (DDE, DDD, mitotane) were docked into the human AR and ER using the Induced Fit docking procedure. The resulting ligand-receptor complexes were clustered and representative complexes were analyzed. The average interaction energy for the DDD, DDT, DDE, and mitotane complexes with AR were calculated to be -26.67, -24.47, -21.86, and -23.48 kcal/mol, respectively. The energy of interactions for the EDCs with the ER are -21.47, -23.58, -19.37, and -21.31 kcal/mol, respectively. These results are in relatively good agreement with experimental IC<sub>50</sub>s for steroid release in the presence of the EDCs. From the residues with strong EDC interaction energy, N833, F673, and P723 were common to all EDC/AR complexes while K481, V478, M315, P365 and G314 were found in the EDC/ER complexes and were inferred to be important for ligand binding. The AR residues I672, P673, and N833 are the topological equivalents of M315, P365, and V478 respectively, in the ER. Mutations are under way to confirm the role and significance of these residues in EDC binding.

Docking study of DDT and analogues in the androgen and estrogen receptor BF-3 surface binding site

255th National Meeting (2018)

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