Virtual screening for inhibitors of human aldose reductase
Virtual screening for inhibitors of human aldose reductase
复制标题
人醛糖还原酶抑制剂的虚拟筛选
DOI：
10.1002/prot.20057
复制
发表时间：
2004
期刊：
影响因子：
--
通讯作者：
G. Klebe
中科院分区：
文献类型：
--
作者：
O. Kraemer;I. Hazemann;A. Podjarny;G. Klebe
醛糖还原酶（AR）的抑制为预防慢性糖尿病并发症提供了一种有趣的策略。尽管已知大量不同的AR抑制剂，但这些化合物中很少在临床试验中表现出足够的疗效。我们基于与人类AR复合物的抑制剂IDD594的超高分辨率晶体结构进行了虚拟筛选。AR在结构不同的底物上大规模运作。为了实现这种明显的混杂性，酶可以相当灵活地适应它的底物。同样，它对抑制剂的结合也具有类似的适应性。我们应用了一个连续的层次过滤器协议来搜索可用化学品目录。在第一步选择中，选择具有功能基团的假设配体来锚定AR的阴离子结合口袋。随后，基于IDD594的结合几何形状和结合口袋的假设“热点”映射的药效团模型被用作第二个连续过滤器。在第三个也是最后一个筛选步骤中，剩余的候选分子被灵活地与FlexX对接到IDD594的结合口袋中，并根据其估计的DrugScore值进行排名。通过聚类分析和目视检查，从206个化合物中选出9个化合物进行生物学测试。其中6个化合物的IC50值在微摩尔范围内。根据所提出的结合模式，BTB02809 （IC50 = 2.4±0.5 μM）和JFD00882 （IC50 = 4.1±1.0 μM）两种抑制剂均将一个硝基放置在人类AR的疏水特异性口袋中，其取向与IDD594的溴原子位置一致。该Br与Thr113的相互作用已被确定为负责选择性增强的关键特征。2004的蛋白质。©2004 Wiley‐Liss, Inc。
The inhibition of aldose reductase (AR) provides an interesting strategy to prevent the complications of chronic diabetes. Although a large number of different AR inhibitors are known, very few of these compounds exhibit sufficient efficacy in clinical trials. We performed a virtual screening based on the ultrahigh resolution crystal structure of the inhibitor IDD594 in complex with human AR. AR operates on a large scale of structurally different substrates. To achieve this pronounced promiscuity, the enzyme can adapt rather flexibly to its substrates. Likewise, it has a similar adaptability for the binding of inhibitors. We applied a protocol of consecutive hierarchical filters to search the Available Chemicals Directory. In the first selection step, putative ligands were chosen that exhibit functional groups to anchor the anion‐binding pocket of AR. Subsequently, a pharmacophore model based on the binding geometry of IDD594 and the mapping of the binding pocket in terms of putative “hot spots” of binding was applied as a second consecutive filter. In a third and final filtering step, the remaining candidate molecules were flexibly docked into the binding pocket of IDD594 with FlexX and ranked according to their estimated DrugScore values. Out of 206 compounds selected by this search and complemented by a cluster analysis and visual inspection, 9 compounds were selected and subjected to biological testing. Of these, 6 compounds showed IC50 values in the micromolar range. According to the proposed binding mode, the two inhibitors BTB02809 (IC50 = 2.4 ± 0.5 μM) and JFD00882 (IC50 = 4.1 ± 1.0 μM) both place a nitro group into the hydrophobic specificity pocket of human AR in an orientation coinciding with the position of the bromine atom of IDD594. The interaction of this Br with Thr113 has been identified as a key feature that is responsible for selectivity enhancement. Proteins 2004. © 2004 Wiley‐Liss, Inc.
精制 1.8 人醛糖还原酶与强效抑制剂佐波尔司他复合的结构。
DOI：
10.1073/pnas.90.21.9847
发表时间：
1993
影响因子：
11.1
作者：
Wilson,DK;Tarle,I;Petrash,JM;Quiocho,FA
通讯作者：
Quiocho,FA
影响因子：
56.9
作者：
David K Wilson;K. Bohren;K. Gabbay;F. Quiocho
通讯作者：
David K Wilson;K. Bohren;K. Gabbay;F. Quiocho
1.7 FR-1 的结构，FR-1 是醛酮还原酶家族的成纤维细胞生长因子诱导的成员，与辅酶和抑制剂复合。
影响因子：
2.9
作者：
Wilson,DK;Nakano,T;Petrash,JM;Quiocho,FA
通讯作者：
Quiocho,FA