title: Molecular modelling studies on d-annulated benzazepinones as VEGF-R2 kinase inhibitors using docking and 3D-QSAR.
abstract: Chemotypes comprising the d-annulated 1,3-dihydro-2H-1-benzazepin-2-one scaffold derived from the paullone structure were found to be potent vascular endothelial growth factor receptor 2 (VEGF-R2) kinase inhibitors. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and docking studies were performed on a series of d-annulated benzazepinones with VEGF-R2 kinase inhibition activities. The comparative molecular field analysis and comparative molecular similarity indices analysis models using 32 molecules in the training set gave r(2)(cv) values of 0.811 and 0.769, r(2) values of 0.962 and 0.953, respectively. 3D contour maps generated from the two models revealed that the electron-withdrawing groups at R(1) and the bulky, electron-withdrawing as well as hydrogen bond donor groups at R(2) position are favourable; the bulky, hydrogen bond acceptor substituent at R(3) and the minor groups at R(4) position may benefit the potency. We have designed a series of novel VEGF-R2 inhibitors by utilizing the SAR results revealed in the present study, which were predicted with excellent potencies in the developed models. The results may aid in designing of potential VEGF-R2 inhibitors with better activities.
authors.affiliation: Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Lan
authors.forename: Jun-Rong
authors.initials: JR
authors.lastname: Sun
authors.forename: Wan-Na
authors.initials: WN
authors.lastname: Chen
authors.forename: Ping-Hua
authors.initials: PH
authors.lastname: Sun
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
mesh_terms: D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017076:Computer-Aided Design; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D001552:Benzazepines; D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2