Exploring the Androgen Receptor Binding Affinity of Azole Derivatives through Multiscale Computational and Experimental Approaches

Azoles are widely used in agriculture to combat fungal pathogens and protect crops. However, their increased use in recent years has raised concerns due to their endocrine-disrupting properties and other toxic effects, posing risks to human, animal, and environmental health. This study sought to characterize the interaction between selected azoles and the androgen receptor (AR) and to assess their impact on the receptor's normal activity. Molecular docking was performed with azoles and dihydrotestosterone (DHT) as reference ligand, followed by molecular mechanics/generalized born surface area (MM/GBSA) analysis of the docked complexes to evaluate their binding affinity with AR. ADMET analysis was conducted for all compounds along with density functional theory calculations, molecular dynamics simulations (MDS), and post-MDS MM/GBSA binding energy calculations for the top six azoles, including DHT, to assess their toxicity, chemical reactivity, structural and conformational stability, mobility, interaction patterns, and binding affinity. Additionally, experimental studies of the top six azoles, based on their affinity for AR, revealed that they inhibited the dimerization of DHT-bound ARs in the cytoplasm and suppressed DHT-induced AR expression. These findings underscore the importance of developing targeted strategies to mitigate the reproductive toxicity of azoles and promote environmental health.