Abstract:
4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as a target for treating type I tyrosinemia and other diseases with defects in tyrosine catabolism. Only one commercial drug, 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC), clinically treat type I tyrosinemia, but show some severe side effects in clinical application. Here, we determined the structure of human HPPD-NTBC complex, and developed new pyrazole-benzothiadiazole 2,2-dioxide hybrids from the binding of NTBC. These compounds showed improved inhibition against human HPPD, among which compound a10 was the most active candidate. The Absorption Distribution Metabolism Excretion Toxicity (ADMET) predicted properties suggested that a10 had good druggability, and was with lower toxicity than NTBC. The structure comparison between inhibitor-bound and ligand-free form human HPPD showed a large conformational change of the C-terminal helix. Furthermore, the loop 1 and α7 helix were found adopting different conformations to assist the gating of the cavity, which explains the gating mechanism of human HPPD.
摘要:
4-羟基苯基丙酮酸双加氧酶(HPPD)作为治疗I型酪氨酸血症和其他酪氨酸分解代谢缺陷疾病的靶标引起了越来越多的关注。只有一种商业药物,2-(2-硝基-4-三氟甲基苯甲酰基)-1,3-环己二酮(NTBC),临床治疗I型酪氨酸血症,但在临床应用中表现出一些严重的副作用。这里,我们确定了人类HPPD-NTBC复合物的结构,并从NTBC的结合中开发了新的吡唑-苯并噻二唑2,2-二氧化杂化物。这些化合物显示出对人类HPPD的改善抑制,其中化合物a10是最活跃的候选化合物。吸收分布代谢排泄毒性(ADMET)预测特性表明,a10具有良好的成药能力,毒性低于NTBC。抑制剂结合和无配体形式的人HPPD之间的结构比较显示C末端螺旋的大构象变化。此外,发现环1和α7螺旋采用不同的构象来辅助腔的门控,这解释了人类HPPD的门控机制。