Novel natural scaffold as hURAT1 inhibitor identified by 3D-shape-based, docking-based virtual screening approach and biological evaluation
Novel natural scaffold as hURAT1 inhibitor identified by 3D-shape-based, docking-based virtual screening approach and biological evaluation
复制标题
通过基于 3D 形状、基于对接的虚拟筛选方法和生物学评估鉴定出作为 hURAT1 抑制剂的新型天然支架
DOI：
10.1016/j.bioorg.2021.105444
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发表时间：
2021-12-01
影响因子：
5.1
通讯作者：
Tian, Yuanxin
中科院分区：
文献类型：
--
作者：
Chen, Xinhua;Zhao, Zean;Tian, Yuanxin
hURAT 1作为痛风治疗的一个新靶点，越来越受到人们的关注。在这项工作中，我们确定了一种新的支架hURAT 1抑制剂从个人天然产品数据库验证草药治疗痛风。首先，我们从中药中构建了800多种天然化合物，这些化合物被证实可以治疗痛风。在应用基于形状和基于对接的虚拟筛选（VS）方法后，考虑到靶标的形状相似性和灵活性，我们确定了可能抑制hURAT 1的异戊烯基二氢黄酮。具体而言，利用生物化学测定法测试了具有商业可用性的9种化合物对高表达hURAT 1细胞（HEK 293-hURAT 1）中C-14-尿酸摄取的抑制作用，并评价了它们的构效关系。结果，8-异戊烯基二氢黄酮被鉴定为hURAT 1抑制剂的新型支架，因为异巴瓦钦（DHF 3）以0.39 +/- 0.17 μ M的IC 50值抑制hURAT 1，其与verinurad相当，IC 50值为0.32 +/- 0.23 μ M。值得注意的是，在体内实验中，异巴瓦钦在血清尿酸的下降中也显示出显著的效果。总的来说，异巴瓦菌素是治疗高尿酸血症和痛风的有希望的候选药物。
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.