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Published on: April 6, 2016
Receptor-based virtual screening of EGFR kinase inhibitors from the NCI diversity database
Kiattawee Choowongkomon1, Orathai Sawatdichaikul, Napat Songtawee
1Department of Biochemistry, Kasetsart University, Bangkok, 10900, Thailand.
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.
Insights
Researchers identified eight novel compounds targeting the Epidermal growth factor receptor tyrosine kinase (EGFR-TK) using virtual screening. These potential anti-cancer drugs exhibit unique binding modes, differing from existing inhibitors.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- Epidermal growth factor receptor (EGFR) abnormalities are linked to various human cancers.
- Understanding EGFR tyrosine kinase (EGFR-TK) inhibition is crucial for developing novel anti-cancer therapeutics.
Purpose of the Study:
- To identify novel small molecules that inhibit EGFR-TK through receptor-based virtual screening.
- To discover potential anti-cancer drug leads with unique binding mechanisms.
Main Methods:
- Virtual screening of 1,990 compounds from the National Cancer Institute (NCI) diversity set against EGFR-TK.
- Utilized AutoDock and Gold docking algorithms, followed by post-docking analyses.
- Evaluated binding modes and interactions within the ATP-competitive site.
Main Results:
- Identified eight high-scoring candidate compounds that bind to the ATP-competitive site of EGFR-TK.
- These compounds are structurally distinct from known EGFR-TK inhibitors, including quinazolines.
- Binding interactions primarily involve hydrophobic forces, with rare hydrogen bonds to the hinge region.
Conclusions:
- The identified compounds represent novel lead structures for anti-cancer drug design.
- Their unique binding modes offer new strategies for targeting EGFR-TK.
- Further development could lead to innovative cancer therapies.
