title: Binding modes of 6,7 di-substituted 4-anilinoquinoline-3-carbonitriles to EGFR.
abstract: 4-Anilino-3-cyanoquinolines were reported to have irreversible binding to epidermal growth factor receptor kinase (EGFRK) by forming a covalent linkage to C773. Our initial docking studies gave results inconsistent with the in vitro data and showed two different binding modes. To perceive the exact mode of binding of these ligands, two models of the ligand-EGFR complexes were considered: (1) reversible binding mode in which the ligand had hydrogen bond interactions at the binding site and (2) irreversible binding mode wherein the ligand's Michael acceptor side chain has proximity to the sulfhydryl group of C773 of EGFR, thereby enabling a covalent interaction. The irreversible binding mode correlated better than reversible binding mode with respect to in vitro data. However, our results indicate that both modes are being adopted by the ligands and could be utilized to design more potent EGFRK inhibitors.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
authors.forename: Nagaraju
authors.initials: N
authors.lastname: Akula
authors.forename: Jag
authors.initials: J
authors.lastname: Bhalla
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Sridhar
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Pattabiraman
mesh_terms: D001665:Binding Sites / Q000502:physiology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006860:Hydrogen Bonding; D008024:Ligands; D009570:Nitriles / Q000138:chemical synthesis*; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D009570:Nitriles; D011804:Quinolines; D066246:ErbB Receptors