title: Receptor-based virtual screening of EGFR kinase inhibitors from the NCI diversity database.
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.
authors.affiliation: Department of Biochemistry, Kasetsart University, Bangkok, 10900, Thailand.
authors.forename: Kiattawee
authors.initials: K
authors.lastname: Choowongkomon
authors.forename: Orathai
authors.initials: O
authors.lastname: Sawatdichaikul
authors.forename: Napat
authors.initials: N
authors.lastname: Songtawee
authors.forename: Jumras
authors.initials: J
authors.lastname: Limtrakul
mesh_terms: D000970:Antineoplastic Agents; D016208:Databases, Factual; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008962:Models, Theoretical; D015394:Molecular Structure; D054547:National Cancer Institute (U.S.); D017433:Protein Structure, Secondary; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors