A Molecular Modeling Study of the Hydroxyflutamide Resistance Mechanism Induced by Androgen Receptor Mutations

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Hydroxyflutamide (HF), an antiandrogen metabolite, treats prostate cancer by targeting the androgen receptor (AR).
• Drug resistance to HF emerges due to AR mutations, notably T877A, W741C_T877A, and F876L_T877A.
• Understanding the molecular mechanisms of HF resistance is crucial for developing effective cancer therapies.

Purpose of the Study:

• To investigate the interaction mechanisms between Hydroxyflutamide (HF) and wild-type (WT) and mutant androgen receptors (ARs).
• To elucidate the role of AR structural dynamics, particularly helix 12 (H12), in mediating HF resistance.
• To identify key residues involved in the agonist/antagonist activity of HF.

Main Methods:

• Molecular dynamics (MD) simulations were employed to model the behavior of HF with WT and mutant ARs.
• The molecular mechanics generalized Born surface area (MM-GBSA) method was used to analyze binding free energies.
• Per-residue free energy decomposition was performed to pinpoint critical amino acid contributions.

Main Results:

• AR helix 12 (H12) dynamics are central to HF resistance, controlling the formation of the coactivator binding site at the activation function 2 (AF2) domain.
• A closed H12 conformation facilitates coactivator binding and transcriptional activity, while an open conformation distorts the site, leading to transcriptional inactivation.
• Residues N705, T877, and M895 were identified as vital for HF's agonist/antagonist mechanism.

Conclusions:

• AR helix 12 (H12) structural dynamics are a key determinant of Hydroxyflutamide (HF) efficacy and resistance in prostate cancer.
• Mutations affecting H12 conformation can lead to drug resistance by preventing proper coactivator recruitment.
• Targeting AR H12 dynamics or specific residues like N705, T877, and M895 may offer new strategies to overcome HF resistance.