Structural and molecular insights into the mechanism of resistance to enzalutamide by the clinical mutants in androgen receptor (AR) in castration-resistant prostate cancer (CRPC) patients

Androgen receptor (AR) is a key contributing element in the prostate cancer (PCa) instigation, progression and it is among the vastly discovered target for prostate cancer. Numerous mechanisms trigger the expansion of CRPC among which the aberrant AR gene is considered as the prime factor. Recently three essential substitutions H875Y, F877L, and T878A are reported to cause resistance to Enzalutamide. However, no detailed study is available to explore the key events that contribute to the resistance. Hence, considering the applicability of structural bioinformatics and molecular simulation-based methods in the current study, we assessed the impact of these mutations on the binding of Enzalutamide. Using a long-run simulation approach the binding stability, residues flexibility, hydrogen bonding, and protein compactness for each complex were determined to reveal the dynamic variations induced by these mutations. We discovered that the binding mode of Enzalutamide is altered by these mutations which misstarget the key residues required for the antagonistic activity. Molecular simulation of each complex revealed that the wild type H11 and H12 are more flexible moving outside and provides more volume for the ligand optimization. In the mutant complexes, the H12 remained tighter pushing out enzalutamide from the key residues which then essentially misstarget the correct orientation for the antagonist activity. The binding free energy (BFE) for the wild type was computed to be -59.92 ± 0.18 kcal/mol, for H875Y the BFE was -55.92 ± 0.18 kcal/mol, -54.82 ± 0.15 kcal/mol for F877L and -53.87 ± 0.18 kcal/mol for T878A, which further demonstrate that these mutations have destabilized the binding of enzalutamide. The proteins' motion and FEL further validated the aforementioned findings where the wild type reported different dynamic features than the mutant complexes. In conclusion, this study provides a structural basis for the resistance to Enzalutamide, which can be used to design novel effective drugs using structure-based and rationale approaches.