Abstract
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.
Highlights
The receptor tyrosine kinase (RTK) of the epidermal growth factor receptor (EGFR, ErbB) family plays a crucial role in cellular signaling pathways that regulate key functions such as differentiation, proliferation, survival and apoptosis [1]
Several inhibitors of Epidermal growth factor receptor (EGFR)-TK have been clinically validated for the treatment of patients with non-small cell lung cancer (NSCLC) and breast cancer during the past several years [37], the search for new active compounds against EGFR-TK is still considerably challenging
Receptor-based virtual screening on EGFR-TK against 128 anilinoquinazoline analogues has been carried out using the crystal structures of erlotinib − EGFR-TK (PDB: 1M17) as a search model [32]
Summary
The receptor tyrosine kinase (RTK) of the epidermal growth factor receptor (EGFR, ErbB) family plays a crucial role in cellular signaling pathways that regulate key functions such as differentiation, proliferation, survival and apoptosis [1]. The crystal structures of EGFR-TK complexed with the drugs erlotinib and gefitinib have been used to explore key binding modes including the hydrogen bonds between the kinase hinge region and the quinazoline moiety of the drugs [17,20]. These studies help us understand the interaction between. Using different molecular docking techniques combined with post-docking analyses, we found eight compounds with high rank scoring functions and their binding modes to EGFR-TK were predicted
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