Molecular dynamics simulations reveal the plausible agonism/antagonism mechanism by steroids on androgen receptor...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Androgen receptors (AR) are crucial drug targets for prostate cancer (PCa).
• Cancer cells can reactivate AR signaling using alternative steroids like glucocorticoids, even with AR-targeting drugs.
• Mutations in the AR gene can cause antagonists to act as agonists, a mechanism needing further elucidation.

Purpose of the Study:

• To investigate the role of bicalutamide conformation in its antagonist function.
• To elucidate the molecular mechanisms by which glucocorticoids revive AR signaling.
• To understand how AR antagonists convert to agonists due to mutations.

Main Methods:

• Molecular dynamics simulations were employed.
• The study focused on bicalutamide, prednisolone, and dexamethasone interactions with the AR.
• Specific attention was given to the AR^L701H mutation.

Main Results:

• A "closed" conformation of bicalutamide is essential for its antagonist activity.
• The W741 residue plays a critical role in maintaining this closed conformation.
• Prednisolone and dexamethasone were shown to mimic the natural agonist DHT, confirming their role in reviving AR signaling.

Conclusions:

• Bicalutamide's efficacy as an AR antagonist is conformation-dependent.
• Glucocorticoids can restore AR signaling, particularly in the presence of specific AR mutations like L701H.
• Understanding these molecular mechanisms is vital for developing more effective prostate cancer therapies.