Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking
Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking
复制标题
DOI：
10.1073/pnas.1131854100
复制
发表时间：
2003-06-10
影响因子：
11.1
通讯作者：
Samuels, HH
中科院分区：
文献类型：
--
作者：
Schapira, M;Raaka, BM;Samuels, HH
甲状腺机能亢进是一种常见的临床疾病，在老年人中可能有严重的表现，治疗方法在30多年来基本保持不变。在受体水平上直接拮抗甲状腺激素的作用可能对甲状腺功能亢进患者的治疗有显著的改善作用。我们建立了预测拮抗剂结合构象的甲状腺激素受体（TR）配体结合结构域的计算机模型，并使用虚拟筛选算法从1,500,000个化合物库中选择100个TR拮抗剂候选物。我们通过硅芯片获得了75种化合物，并通过培养表达TR的细胞研究了它们作为拮抗剂的能力。其中14种化合物被发现可以拮抗T3对TR的作用，其IC(50)s范围为1.5至30 muM。从最高亲和拮抗剂（1-850）衍生出一个小的虚拟化合物库，可以快速合成。第二轮虚拟筛选确定了预测拮抗剂活性增加的新化合物。合成了这些第二代化合物，并通过转染和受体结合实验证实了它们作为TR拮抗剂的能力。拮抗剂化合物的极端结构多样性表明基于受体的虚拟筛选如何能够识别符合TR拮抗剂结构规则的多种化学物质。
Treatment of hyperthyroidism, a common clinical condition that can have serious manifestations in the elderly, has remained essentially unchanged for >30 years. Directly antagonizing the effect of the thyroid hormone at the receptor level may be a significant improvement for the treatment of hyperthyroid patients. We built a computer model of the thyroid hormone receptor (TR) ligand-binding domain in its predicted antagonist-bound conformation and used a virtual screening algorithm to select 100 TR antagonist candidates out of a library of >250,000 compounds. We were able to obtain 75 of the compounds selected in silico and studied their ability to act as antagonists by using cultured cells that express TR. Fourteen of these compounds were found to antagonize the effect of T3 on TR with IC(50)s ranging from 1.5 to 30 muM. A small virtual library of compounds, derived from the highest affinity antagonist (1-850) that could be rapidly synthesized, was generated. A second round of virtual screening identified new compounds with predicted increased antagonist activity. These second generation compounds were synthesized, and their ability to act as TR antagonists was confirmed by transfection and receptor binding experiments. The extreme structural diversity of the antagonist compounds shows how receptor-based virtual screening can identify diverse chemistries that comply with the structural rules of TR antagonism.