Dong Jin, Xiao Han, Chen Jia-Nan, Zheng Bai-Feng, Xu Yu-Ling, Chen Meng-Xi, Yang Wen-Chao, Lin Hong-Yan, Yang Guang-Fu
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan 430079, P.R.China.
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan 430079, P.R.China.
Structure. 2023 Dec 7;31(12):1604-1615.e8. doi: 10.1016/j.str.2023.09.005. Epub 2023 Oct 3.
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.
4-羟基苯丙酮酸双加氧酶（HPPD）作为治疗I型酪氨酸血症及其他酪氨酸分解代谢缺陷疾病的靶点，已受到越来越多的关注。临床上治疗I型酪氨酸血症的药物仅有2-(2-硝基-4-三氟甲基苯甲酰基)-1,3-环己二酮（NTBC）这一种，但在临床应用中显示出一些严重的副作用。在此，我们确定了人源HPPD-NTBC复合物的结构，并基于NTBC的结合开发了新型吡唑-苯并噻二唑2,2-二氧化物杂合物。这些化合物对人源HPPD的抑制作用有所改善，其中化合物a10是最具活性的候选物。吸收、分布、代谢、排泄、毒性（ADMET）预测特性表明a10具有良好的成药性，且毒性低于NTBC。抑制剂结合型与人源HPPD游离配体形式的结构比较显示C末端螺旋发生了较大的构象变化。此外，发现环1和α7螺旋采取不同构象以辅助腔门控，这解释了人源HPPD的门控机制。
