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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

Department of Biochemistry, Kasetsart University, Bangkok, 10900, Thailand
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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