Novel natural scaffold as hURAT1 inhibitor identified by 3D-shape-based, docking-based virtual screening approach and biological evaluation

作者：Chen, Xinhua; Zhao, Zean; Luo, Jiajun; Wu, Ting; Shen, Yudong; Chang, Shan; Wan, Shanhe; Li, Zhonghuang; Zhang, Jiajie^*; Pang, Jianxin^*; Tian, Yuanxin^*

来源：Bioorganic Chemistry, 2021, 117: 105444.

DOI：10.1016/j.bioorg.2021.105444

• Hyperuricemia
• URAT1
• Virtual screening
• Isoprenylated dihydroflavone
• Isobavachin

As a promising therapeutic target for gout, hURAT1 has attracted increasing attention. In this work, we identified a novel scaffold of hURAT1 inhibitors from a personal natural product database of verified herb-treated gout. First, we constructed more than 800 natural compounds from Chinese medicine that were verified to treat gout. Following the application of both shape-based and docking-based virtual screening (VS) methods, taking into account the shape similarity and flexibility of the target, we identified isopentenyl dihydroflavones that might inhibit hURAT1. Specifically, 9 compounds with commercial availability were tested with biochemical assays for the inhibition of C-14-uric acid uptake in high-expression hURAT1 cells (HEK293-hURAT1), and their structure-activity relationship was evaluated. As a result, 8-isopentenyl dihydroflavone was identified as a novel scaffold of hURAT1 inhibitors since isobavachin (DHF3) inhibited hURAT1 with an IC50 value of 0.39 +/- 0.17 mu M, which was comparable to verinurad with an IC50 value of 0.32 +/- 0.23 mu M. Remarkably, isobavachin also displayed an eminent effect in the decline of serum uric acid in vivo experiments. Taken together, isobavachin is a promising candidate for the treatment of hyperuricemia and gout.

• 单位
  南方医科大学; 江苏大学; 华南农业大学