Abstract:
Occupancy of prostate cancer (PCa) cell androgen receptors (AR) signals proliferation, therefore testosterone biosynthesis inhibitors and AR antagonists are important PCa treatments. Conversely, androgen mimics (e.g., prednisone) used in management of PCa might cause proliferation. The balance between PCa proliferation and inhibition predicts treatment success. We used in silico molecular modelling to explore interactions between ARs, androgens (testosterone, dihydrotestosterone (DHT)) and drugs used to treat (bicalutamide) and manage (dexamethasone, prednisone, hydrocortisone) PCa. We found that hydrogen (H-) bonds between testosterone, DHT and Arg752, Asn705 and Thr877 followed by ligand binding cleft hydrophobic interactions signal proliferation, whereas bicalutamide antagonism is via Phe764 interactions. Hydrocortisone, dexamethasone and prednisone H-bond Asn705 and Thr877, but not Arg752 in the absence of a water molecule. Studies with a bicalutamide agonist AR mutation showed different amino acid interactions, indicating testosterone and DHT would not promote proliferation as effectively as via the native receptor. However, hydrocortisone and bicalutamide form Arg752 and Asn705 H-bonds indicating agonism. Our results suggest that as PCa progresses the resulting mutations will change the proliferative response to androgens and their drug mimics, which have implications for the treatment of prostate cancer.
摘要:
占用前列腺癌(PCa)细胞雄激素受体(AR)信号增殖,因此睾酮生物合成抑制剂和AR拮抗剂是重要的PCa治疗方法。相反,雄激素模仿(例如,泼尼松)用于PCa的管理可能会引起增殖。PCa增殖和抑制之间的平衡预测治疗成功。我们在硅分子建模中探索AR之间的相互作用,雄激素(睾酮,双氢睾酮(DHT))和用于治疗(比卡鲁胺)和管理(地塞米松,泼尼松,氢化可的松)PCa。我们发现睾酮之间的氢键,DHT与Arg752、Asn705和Thr877跟随配体结合裂隙疏水相互作用信号增殖,而比卡鲁胺拮抗作用是通过Phe764相互作用。氢化可的松,在没有水分子的情况下,地塞米松和泼尼松H键Asn705和Thr877,而不是Arg752。比卡鲁胺激动剂AR突变的研究显示不同的氨基酸相互作用,表明睾酮和DHT不能像通过天然受体那样有效地促进增殖。然而,氢化可的松和比卡鲁胺形成Arg752和Asn705的H-键,表明激动作用。我们的结果表明,随着PCa的进展,所产生的突变将改变对雄激素及其药物模拟物的增殖反应。这对前列腺癌的治疗有影响。