For fragment-based cancer drug discovery, we introduced a molecular docking simulation combined with a protein chip assay. Protein chip technology was used to find fragment-hits that had inhibitory activity against Bcl-2 protein from 131 pre-selected fragment chemicals. Molecular docking simulation was performed for the 12 identified fragment-hits to establish the binding mode of these compounds in the Bcl-2 site. Using the molecular docking-assisted protein chip screening system, we derived a virtual compound structure with an important scaffold feature for interaction with the Bcl-2 protein. We then tested the anticancer activity of 26 compounds that were similar to the scaffold structure. The anticancer activity was confirmed by MTT-assay in A549 lung cancer cells. Finally, three chemicals showed dose-dependent inhibitory activity against cancer cell proliferation. We suggest that the present molecular docking-assisted protein chip assay can be used as a platform technology in the fragment-based drug development process to discover inhibitory agents of protein-protein interactions.

中文翻译：

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Bcl-2家族蛋白相互作用的抑制剂的分子对接辅助蛋白芯片筛选，以基于片段的方法发现抗癌药

对于基于片段的癌症药物发现，我们引入了结合蛋白质芯片测定的分子对接模拟。蛋白芯片技术用于从131种预选片段化学物中寻找对Bcl-2蛋白具有抑制活性的片段。对12个已鉴定的片段进行分子对接模拟，以建立这些化合物在Bcl-2位点的结合模式。使用分子对接辅助蛋白芯片筛选系统，我们得到了具有重要支架特征的虚拟化合物结构，该结构与Bcl-2蛋白相互作用。然后，我们测试了26种与支架结构相似的化合物的抗癌活性。通过MTT测定法在A549肺癌细胞中证实了抗癌活性。最后，三种化学物质对癌细胞的增殖显示出剂量依赖性的抑制活性。我们建议本分子对接辅助的蛋白质芯片测定法可以用作基于片段的药物开发过程中的平台技术，以发现蛋白质-蛋白质相互作用的抑制剂。