a School of Pharmacy , Lanzhou University , Lanzhou , China.
J Biomol Struct Dyn. 2018 Aug;36(11):2876-2892. doi: 10.1080/07391102.2017.1371643. Epub 2017 Sep 13.
Prostate cancer (PCa) is a frequently diagnosed male cancer and the second leading cause of cancer-related death in many countries. Due to various amino acid mutations that occurred in the ligand binding domain of androgen receptor (AR), the patients were observed insensitive, even resistant to the marketed antiandrogens such as bicalutamide and enzalutamide, which emphasizes the urgent need for novel antiandrogens to solve drug resistance problem. Recently a series of carbobicyclo and oxabicyclo succinimide analogs were reported to effectively antagonize AR. In this study, to explore the structural requirements for these AR antagonists, we performed quantitative structure-activity relationship analysis on carbobicyclo and oxabicyclo succinimide analogs by using two-dimensional multiple linear regressions (MLR) method and three-dimension comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. The obtained models show satisfactory results with proper reliabilities and powerful external predictability. Moreover, the CoMFA and CoMSIA contour maps can intuitively represent key features associated with bioactivities. These models may offer guidance for the rational design and modification of new lead compounds for antiandrogens.
前列腺癌（PCa）是一种常见的男性癌症，也是许多国家癌症相关死亡的第二大主要原因。由于雄激素受体（AR）配体结合域发生了各种氨基酸突变，患者表现出不敏感，甚至对已上市的抗雄激素药物如比卡鲁胺和恩杂鲁胺产生耐药性，这强调了迫切需要新型抗雄激素药物来解决耐药性问题。最近，一系列碳环双环和氧杂双环琥珀酰亚胺类似物被报道能有效拮抗 AR。在这项研究中，为了探索这些 AR 拮抗剂的结构要求，我们通过二维多元线性回归（MLR）方法以及三维比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）方法对碳环双环和氧杂双环琥珀酰亚胺类似物进行了定量构效关系分析。所获得的模型具有适当的可靠性和强大的外部预测能力，结果令人满意。此外，CoMFA 和 CoMSIA 等高线图可以直观地表示与生物活性相关的关键特征。这些模型可能为新型抗雄激素药物的合理设计和修饰提供指导。
