Endocrine Abstracts

JOINT856

Introduction: Androgen hormones play a central role in the development and maintenance of male reproductive functions by interacting with the androgen receptor (AR). The AR regulates the transcription of genes associated with sexual differentiation, development of secondary characteristics, and tissue homeostasis. This protein comprises four main domains: the amino-terminal domain, DNA-binding domain, hinge region, and ligand-binding domain (LBD). The LBD is responsible for interactions with steroid hormones, drugs, and xenobiotic molecules, such as endocrine disruptors (EDs). EDs are environmental compounds capable of mimicking or antagonizing natural hormones, thereby affecting endocrine pathways. Some EDs, such as Bisphenol A, Tributyltin, MEHP, and Atrazine, have been shown to interact with the AR’s LBD, modulating its function and altering physiological processes involving androgens. However, further exploration of the molecular interactions between EDs and the AR’s LBD is still required. Molecular docking models represent a promising approach to investigate the extent of these interactions and establish correlations with the disruptive potential of various EDs on reproductive functions.

Objective: To evaluate the type and affinity of interactions between different EDs and the amino acids of the AR’s LBD using molecular modeling tools.

Methodology: Ten EDs and ten known agonists with androgenic or anti-androgenic activity were selected. The three-dimensional structures were obtained in mol2 format from the PubChem and ChEMBL databases. The three-dimensional model of the AR’s LBD was derived from crystallographic structures available in the PDB. Molecular docking studies were conducted using the GOLD software, employing the GoldScore scoring algorithm for result validation. The stability of the complexes was assessed by measuring hydrophobic interactions, hydrogen bonds, and dipole-dipole interactions using PyMOL and Discovery Studio.

Results: The most relevant amino acids for the stabilization of the reference agonists identified were T877, N705, R752, and Q711. Certain EDs, such as DBP, MEHP, BPS, and BPA, showed strong similarities in their interactions with these polar residues. In contrast, Irgarol, Tributyltin, and DDT demonstrated stabilization through predominantly nonpolar interactions involving M745, L704, L873, and W741. Although these interactions are less frequently described in the literature, the resulting conformations were structurally stable, suggesting an alternative modulation potential for the receptor.

Conclusion: This study contributes to the understanding of the interactions between EDs and the AR’s LBD. Docking analysis indicated that different classes of EDs may exhibit varied interaction profiles with LBD amino acids, highlighting the need for further studies to evaluate their functional and toxicological impacts.