Enstitü öğretim üyelerimizden Dr. Öğr. Üyesi Sefer Baday'ın yazarları arasında olduğu 'Investigation of Drug Resistance Mechanisms for Antiandrogen Prostate Cancer Drug Enzalutamide using Molecular Dynamics Simulations
' başlıklı makale 'Biophysical Journal' dergisinde 2020/2/7 tarihinde yayınlanmıştır.
DOI: https://doi.org/10.1016/j.bpj.2019.11.1173 Özet:
Prostate cancer is the most common cancer type in males after lung-cancer. It is a leading death reason amongst cancer- related deaths. Several drug molecules have been developed for the treatment of prostate cancer. Among those, Enzalutamide molecule is the most recent and potent one. In clinical studies, Enzalutamide therapy reduced significantly radiographic progression and delayed the need for chemotherapy. Despite this success, recently it has been discovered that drug resistance against Enzalutamide occurred. Development and progression of the prostate cancer depends on the androgen stimulation. Therefore, antiandrogen drug molecules target and inhibit Androgen Receptor (AR) signaling function. Enzalutamide properly inhibits AR signaling in wild-type ARs, however a point mutation F876L abolishes the antagonistic activity of enzalutamide. The molecular mechanisms of this resistance remain elusive. Thus, we investigated the mechanism of this resistance at the molecular level using Molecular Dynamics (MD) simulations. We performed one micro-second long classical and accelerated MD simulations of WT-AR, AR with Testosterone and, several AR mutants in complex with Enzalutamide. The experimental structure of AR-Enzalutamide complex has not been solved yet. Thus, prior to MD simulation we performed docking of Enzalutamide.Current studies suggest that displacement or instability of the helix 12 might be causing the switch between antagonist to agonist activity. However, what interactions lead to the instability of helix12 have not been understood clearly. Our simulations suggest that unbending of helix 11 ( at the crystal structure it is in bend structure) could lead to the loss in stability of helix 12. In the simulations of apo AR and AR with Testosterone, the unbending is rare. On the contrary, the simulations of AR with enzalutamide, particularly with mutations abolishing antagonist activity, the unbending of helix 11 becomes too frequent.