Receptor-Based Virtual Screening of EGFR Kinase Inhibitors from the NCI Diversity Database
Receptor-Based Virtual Screening of EGFR Kinase Inhibitors from the NCI Diversity Database
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DOI：
10.3390/molecules15064041
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发表时间：
2010-06-01
期刊：
影响因子：
4.6
通讯作者：
Limtrakul, Jumras
中科院分区：
文献类型：
--
作者：
Choowongkomon, Kiattawee;Sawatdichaikul, Orathai;Limtrakul, Jumras
表皮生长因子受体(EGFR)的异常与多种类型的人类癌症有关。其酪氨酸激酶结构域(EGFR-TK)与小分子抑制剂结合后的晶体结构揭示了该酶的抑制模式，促使我们寻找新的抗癌药物。来自美国国家癌症研究所(NCI)多样性组的1,990种化合物具有非冗余结构，已被测试以抑制机制未知的癌细胞株。通过EGFR-TK抑制肿瘤是这些化合物的作用机制之一。在这项工作中，我们对NCI多样性数据库进行了基于受体的虚拟筛选。使用两种不同的对接算法，AutoDock和Gold，结合随后的对接后分析，我们发现了八个具有高得分功能的候选化合物，它们都与激酶的ATP竞争位点结合。这些化合物都不属于目前已知的EGFR-TK抑制剂的主要基团。结合模式分析表明，这些化合物与EGFR-TK的结合方式不同于与喹唑啉抑制剂的结合方式，相互作用主要涉及疏水作用。此外，在铰链区和HIT化合物之间很少观察到常见的激酶抑制剂(NH-N和CO-HC)氢键。我们的结果表明，这些分子可以被开发为抗癌药物设计的新型先导化合物。
Epidermal growth factor receptor (EGFR) abnormalities have been associated with several types of human cancer. The crystal structures of its tyrosine kinase domain (EGFR-TK) complexed with small molecule inhibitors revealed the kinase inhibition modes, prompting us to search for novel anti-cancer drugs. A total of 1,990 compounds from the National Cancer Institute (NCI) diversity set with nonredundant structures have been tested to inhibit cancer cell lines with unknown mechanism. Cancer inhibition through EGFR-TK is one of the mechanisms of these compounds. In this work, we performed receptor-based virtual screening against the NCI diversity database. Using two different docking algorithms, AutoDock and Gold, combined with subsequent post-docking analyses, we found eight candidate compounds with high scoring functions that all bind to the ATP-competitive site of the kinase. None of these compounds belongs to the main group of the currently known EGFR-TK inhibitors. Binding mode analyses revealed that the way these compounds complexed with EGFR-TK differs from quinazoline inhibitor binding and the interaction mainly involves hydrophobic interactions. Also, the common kinase-inhibitor (NH---N and CO---HC) hydrogen bonds between the hinge region and the hit compounds are rarely observed. Our results suggest that these molecules could be developed as novel lead compounds in anti-cancer drug design.