title: Elucidating inhibitory models of the inhibitors of epidermal growth factor receptor by docking and 3D-QSAR.
abstract: Epidermal growth factor receptor (EGFR) protein tyrosine kinases (PTKs) are attractive targets for anti-tumor drug design. Although thousands of their ligands have been studied as potential inhibitors against PTKs, there is no QSAR study that covers different kinds of inhibitors with observable structural diversity. However, by using this approach, we could mine far more useful information. Hence in order to better understand the binding model and the relationship between the physicochemical properties and the inhibitory activities of different kind of various inhibitors, molecular docking and 3D-QSAR, viz. CoMFA and CoMSIA, were combined to study 124 reported inhibitors with different scaffolds. Based on the docked binding conformations, highly reliable and predictive 3D-QSAR models were derived, which reveal how steric, electrostatic, and hydrophobic interactions contribute to inhibitors' bioactivities. This result also demonstrates that it is possible to include different kinds of inhibitors with observable structural diversity into one 3D-QSAR study. Therefore, this study not only casts light on binding mechanism between EGFR and its inhibitors, but also provides new hints for de novo design of new EGFR inhibitors with observable structural diversity.
authors.affiliation: Drug Discovery & Design Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Chum Mok
authors.initials: CM
authors.lastname: Puah
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D066246:ErbB Receptors