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Molecules 2010, 15(6), 4041-4054; doi:10.3390/molecules15064041

Receptor-Based Virtual Screening of EGFR Kinase Inhibitors from the NCI Diversity Database

1,* , 1
1 Department of Biochemistry, Kasetsart University, Bangkok, 10900, Thailand 2 Department of Chemistry, Kasetsart University, Bangkok 10900, Thailand
* Author to whom correspondence should be addressed.
Received: 16 March 2010 / Revised: 26 May 2010 / Accepted: 28 May 2010 / Published: 4 June 2010
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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.
Keywords: EGFR-TK; anti-cancer drugs; NCI diversity set; virtual screening; docking EGFR-TK; anti-cancer drugs; NCI diversity set; virtual screening; docking
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Choowongkomon, K.; Sawatdichaikul, O.; Songtawee, N.; Limtrakul, J. Receptor-Based Virtual Screening of EGFR Kinase Inhibitors from the NCI Diversity Database. Molecules 2010, 15, 4041-4054.

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