Identification of small molecular weight inhibitors of Src homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) via in silico database screening combined with experimental assay.
Identification of small molecular weight inhibitors of Src homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) via in silico database screening combined with experimental assay.
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DOI：
10.1021/jm800229d
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发表时间：
2008-12-11
影响因子：
7.3
通讯作者：
Qu CK
中科院分区：
文献类型：
--
作者：
Yu WM;Guvench O;Mackerell AD;Qu CK
虚拟筛选方法与实验测定相结合，用于鉴定含 Src 同源 2 结构域的磷酸酶 2 (SHP-2) 的低分子量抑制剂，该酶在努南综合征和大部分儿童白血病中发生突变和过度激活。虚拟筛选包括蛋白质的多种构象、评分标准化程序和化学相似性考虑因素。由于 SHP-2 的催化核心与相关 SHP-1 磷酸酶和其他酪氨酸磷酸酶具有极高的同源性，为了识别选择性抑制剂，我们选择靶向相邻的蛋白质表面口袋，预计该蛋白质表面口袋对于与磷酸肽的结合非常重要，并且具有 SHP-2 独特的结构特征。从包含 130 万种化合物的数据库中，计算选择的 165 种化合物中的 9 种显示出抑制 SHP-2 活性，IC50 值约为 100 μM。其中两种活性化合物抑制 SHP-2 介导的细胞功能的能力得到了进一步验证。荧光滴定实验证实它们与SHP-2直接结合。由于其简单的化学结构，这些小有机化合物有潜力作为开发新型抗 SHP-2 药物的先导化合物。
Virtual screening methods combined with experimental assays were used to identify low molecular weight inhibitors for Src homology 2 domain-containing phosphatase 2 (SHP-2) that is mutated and hyperactivated in Noonan syndrome and a significant portion of childhood leukemias. Virtual screening included multiple conformations of the protein, score normalization procedures, and chemical similarity considerations. As the catalytic core of SHP-2 shares extremely high homology to those of the related SHP-1 phosphatase and other tyrosine phosphatases, in order to identify selective inhibitors, we chose to target an adjacent protein surface pocket that is predicted to be important for binding to phospho-peptides and that has structural features unique to SHP-2. From a database of 1.3 million compounds, 9 out of 165 computationally selected compounds were shown to inhibit SHP-2 activity with IC50 values of ≈ 100 μM. Two of the active compounds were further verified for their ability to inhibit SHP-2-mediated cellular functions. Fluorescence titration experiments confirmed their direct binding to SHP-2. Because of their simple chemical structures, these small organic compounds have the potential to act as lead compounds for the development of novel anti-SHP-2 drugs.
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影响因子：
56.9
作者：
CONNOLLY, ML
通讯作者：
CONNOLLY, ML
影响因子：
7.3
作者：
GOODFORD, PJ
通讯作者：
GOODFORD, PJ
影响因子：
20.3
作者：
Chan, RJ;Leedy, MB;Kapur, R
通讯作者：
Kapur, R
影响因子：
3.7
作者：
JARVIS, RA;PATRICK, EA
通讯作者：
PATRICK, EA
影响因子：
3
作者：
LEACH, AR;KUNTZ, ID
通讯作者：
KUNTZ, ID