In Silico Exploration of the Endocrine-Disrupting Potential of Phthalate Esters through Structural Interaction with the Human Androgen Receptor

Phthalate esters are ubiquitous environmental pollutants with a well-documented potential to disrupt steroid hormone signaling, particularly through interactions with the human androgen receptor (hAR). This study used a structure-based virtual screening approach to evaluate phthalates using testosterone as the reference ligand. Three independent molecular docking platforms were used to assess binding affinity and pose consistency. The top-ranked compound underwent further investigation, including the analysis of quantum chemical descriptors, molecular dynamics (MD) simulations, binding free energy estimation, <i>per-residue</i> energy decomposition, and noncovalent interaction profiling. Biphenyl phthalate emerged as the leading candidate, exhibiting electrophilicity and electron-accepting capacity greater than that of testosterone, suggesting an enhanced potential for receptor engagement. MD simulations demonstrated that the biphenyl phthalate-hAR complex maintained structural stability comparable to that of testosterone-bound complex. Although MM/PBSA analysis indicated a stronger binding affinity for testosterone, primarily due to electrostatic and hydrogen-bond interactions, biphenyl phthalate binding was predominantly stabilized by van der Waals forces. These contrasting interaction patterns were further supported by energy decomposition and noncovalent interaction analyses. In conclusion, biphenyl phthalate mimics key structural and electronic features of testosterone, supporting its ability to engage hAR and reinforcing its potential classification as an endocrine-disrupting compound.