Kocak Abdulkadir, Yildiz Muslum
Department of Chemistry, Gebze Technical University, 41400, Kocaeli, Turkey.
Department of Molecular Biology and Genetics, Gebze Technical University, 41400, Kocaeli, Turkey.
J Mol Graph Model. 2022 Mar;111:108081. doi: 10.1016/j.jmgm.2021.108081. Epub 2021 Nov 19.
Androgen receptors (AR) are the primary drug target in prostate cancer (PCa). There are several drugs developed against its activity for prostate cancer treatment, but cancer cells revive AR signaling against those drugs by using alternative steroids such as glucocorticoids. In addition, antagonists become agonists due to emergence of mutations in AR gene. The mechanism by which antagonists are converted into agonists and how AR signaling is recovered by other steroids has yet to be fully elucidated. In this study, we interrogated the role of bicalutamide conformation in its antagonist function and how glucocorticoids such as prednisolone and dexamethasone revive AR signaling at the molecular level by means of molecular dynamics. We found that the ''closed'' conformation of bicalutamide is essential for its antagonist function and W741 residue is forcing it into this conformation. Moreover, we show that prednisolone and dexamethasone behave like natural agonist DHT which confirm the experimental results that show their role in the reviving AR signaling in the case of AR mutation.
雄激素受体（AR）是前列腺癌（PCa）的主要药物靶点。已经开发了几种针对其活性用于前列腺癌治疗的药物，但癌细胞通过使用诸如糖皮质激素等替代类固醇来恢复针对这些药物的AR信号传导。此外，由于AR基因中出现突变，拮抗剂会变成激动剂。拮抗剂如何转化为激动剂以及其他类固醇如何恢复AR信号传导的机制尚未完全阐明。在本研究中，我们通过分子动力学研究了比卡鲁胺构象在其拮抗剂功能中的作用，以及泼尼松龙和地塞米松等糖皮质激素如何在分子水平上恢复AR信号传导。我们发现比卡鲁胺的“封闭”构象对其拮抗剂功能至关重要，并且W741残基将其强制成这种构象。此外，我们表明泼尼松龙和地塞米松的行为类似于天然激动剂双氢睾酮（DHT），这证实了实验结果，即显示它们在AR突变情况下恢复AR信号传导中的作用。
