Pharmacophore Modeling and Virtual Screening of Novel Inhibitors for c‐Kit Kinase
Pharmacophore Modeling and Virtual Screening of Novel Inhibitors for c‐Kit Kinase
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DOI：
10.1002/cjoc.201090208
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发表时间：
2010-07
影响因子：
5.4
通讯作者：
Qinglin Jiang;Qian Yang;Changjun Liao;Wang Zan;Zhihe Zang
中科院分区：
文献类型：
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作者：
Qinglin Jiang;Qian Yang;Changjun Liao;Wang Zan;Zhihe Zang
众所周知，干细胞因子受体 (c-Kit) 在调节细胞行为的许多方面发挥着关键作用，包括细胞生长、分化、迁移和代谢。在本研究中，通过使用催化剂软件包中实现的 HypoGen 算法建立了 c-Kit 抑制剂的三维药效团模型。最佳定量药效团模型假设 1 具有最高的相关系数 (0.989)，由 1 个氢键受体、2 个氢键供体和 1 个疏水特征组成。据我们所知，这是第一份关于c-Kit抑制剂药效团模型研究的报告。最好的假设，即假设 1，用于筛选分子结构数据库，包括 Specs 和中国天然产物数据库，以寻找潜在的先导化合物。随后根据 Lipinski 规则和对接研究对命中化合物进行过滤，以细化检索到的命中化合物，从而降低假阳性率。最后购买或合成了 28 种化合物，用于针对几种人类肿瘤细胞系（包括 A549、MCF-7、HepG2 和 PC-3）进行进一步体外测定，其中 c-Kit 过表达。两种化合物分别对 PC-3 和 HepG2 细胞系显示出非常低的微摩尔抑制效力。他们被选中进行进一步的修改和测试。
The stem cell factor receptor (c-Kit) has been known to play critical roles in regulating numerous aspects of cellular behavior including cell growth, differentiation, migration and metabolism. In this investigation, a three-dimensional pharmacophore model of c-Kit inhibitors has been established by using the HypoGen algorithms implemented in the catalyst software package. The best quantitative pharmacophore model, hypothesis 1, which has the highest correlation coefficient (0.989), consists of one hydrogen bond acceptor, two hydrogen bond donors and one hydrophobic feature. To our knowledge, this is the first report on the pharmacophore modeling study of c-Kit inhibitors. The best hypothesis, hypothesis 1, was used to screen molecular structural databases, including Specs and China Natural Products Database for potential lead compounds. The hit compounds were subsequently subjected to filtering by Lipinski's rules and docking study to refine the retrieved hits and as a result to reduce the rate of false positive. Finally 28 compounds were purchased or synthesized for further in vitro assay against several human tumour cell lines including A549, MCF-7, HepG2 and PC-3, in which c-Kit is overexpressed. Two compounds show very low micromolar inhibition potency against the PC-3 and HepG2 cell lines respectively. And they were selected for further modification and testing.