Exploring the relationship between the androgen receptor and structural configuration of benzophenones: a combination of computational analysis and laboratory models

Abstract

This study explored the interactions between benzophenones (BPs) and androgen receptors (AR) using computational and experimental approaches. BPs are potential endocrine disruptors that are commonly found in cosmetics, such as sunscreen. Molecular docking and molecular mechanics with generalized Born and surface area continuum solvation calculations revealed that dihydroxylation form of BP-1, BP-2 had higher binding affinities to AR compared with BP-1, BP-3. Key interactions with residues, such as Gln711 and Asn705, were identified. Density functional theory analysis revealed that BP-2 has a balanced energy gap, which contributes to its stability and reactivity. Cell-based assays validated these computational results, showing that BP-2 had stronger AR antagonistic effect than BP-1 and BP-3. Furthermore, BP-2 enhances the AR-mediated luciferase signal at specific concentration through inducing dimerization of cytosolic AR, whereas BP-1 and BP-3 had no AR agonistic effects. These changes in AR-mediated transcriptional activation activity were observed in flutamide and hydroxyflutamide as well. As expected, changes in AR-mediated endocrine disrupting potential due to configurational modification of BP-1 to BP-2 by dihydroxylation resulted in whole AR protein expression. These findings suggest that BP-2 is a strong AR modulator and a potential endocrine disruptor, offering insights into how similar compounds may interact with AR.