Molecular Dynamics Studies on the Enzalutamide Resistance Mechanisms Induced by Androgen Receptor Mutations

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Enzalutamide, a second-generation antiandrogen, targets the androgen receptor (AR) for castration-resistant prostate cancer (CRPC) treatment.
• Clinical resistance to enzalutamide is a significant challenge, often associated with mutations in the AR.
• Specific AR mutations, like F876L and F876L_T877A, can convert enzalutamide from an antagonist to an agonist.

Purpose of the Study:

• To investigate the interaction mechanisms between enzalutamide and wild-type (WT) and mutant ARs.
• To elucidate how AR ligand-binding domain (LBD) mutations contribute to enzalutamide resistance.
• To explore the role of AR helix 12 (H12) in mediating enzalutamide's agonist/antagonist activity.

Main Methods:

• Molecular dynamics (MD) simulations were used to model enzalutamide-AR interactions.
• Molecular mechanics Generalized Born surface area (MM-GBSA) calculations assessed binding free energies.
• Per-residue free energy decomposition analysis identified key residues involved in drug resistance.

Main Results:

• AR helix 12 (H12) plays a critical role in enzalutamide's mechanism of action.
• Enzalutamide acts as an antagonist when it prevents H12 closure, inhibiting transcription.
• Enzalutamide can act as an agonist if H12 closes, facilitating transcription, particularly with certain AR mutations.
• Residues M895 and I899 were identified as crucial for enzalutamide's antagonist activity.

Conclusions:

• AR mutations can alter enzalutamide's function, leading to treatment resistance.
• The conformational state of AR helix 12 is a key determinant of enzalutamide efficacy.
• Understanding these molecular mechanisms can inform the development of strategies to overcome enzalutamide resistance in CRPC.