title: Design of EGFR kinase inhibitors: a ligand-based approach and its confirmation with structure-based studies.
abstract: Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed for 100 anilinoquinazolines, inhibiting epidermal growth factor receptor (EGFR) kinase. The studies included molecular field analysis (MFA) and receptor surface analysis (RSA). The cross-validated r2 (r2cv) values are 0.81 and 0.79 for MFA and RSA, respectively. The predictive ability of these models was validated by 28 test set molecules. The results of the best QSAR model were further compared with structure-based investigations using docking studies with the crystal structure of EGFR kinase domain. The results helped to understand the nature of substituents at the 6- and 7-positions, thereby providing new guidelines for the design of novel inhibitors.
authors.affiliation: School of Chemistry, University of Hyderabad, Hyderabad 500 046, India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Vema
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Panigrahi
authors.forename: G
authors.initials: G
authors.lastname: Rambabu
authors.forename: B
authors.initials: B
authors.lastname: Gopalakrishnan
authors.forename: J A R P
authors.initials: JA
authors.lastname: Sarma
authors.forename: Gautam R
authors.initials: GR
authors.lastname: Desiraju
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006860:Hydrogen Bonding; D008024:Ligands; D008956:Models, Chemical; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D008024:Ligands; D011799:Quinazolines; D066246:ErbB Receptors