title: Investigation of a novel molecular descriptor for the lead optimization of 4-aminoquinazolines as vascular endothelial growth factor receptor-2 inhibitors: application for quantitative structure-activity relationship analysis in lead optimization.
abstract: We investigated the use of infrared vibrational frequency of ligands as a potential novel molecular descriptor in three different molecular target and chemical series. The vibrational energy of a ligand was approximated from the sum of infrared (IR) absorptions of each functional group within a molecule and normalized by its molecular weight (MDIR). Calculations were performed on a set of 4-aminoquinazolines with similar docking scores for the VEGFR2/KDR receptor. 4-Aminoquinazolines with MDIR values ranging 192-196 provided compounds with KDR inhibitory activity. The correlation of KDR inhibitory activity was similarly observed in a separate chemical series, the pyrazolo[1,5-a]pyrimidines. Initial exploration of this molecular descriptor supports a tool for rapid lead optimization in the 4-aminoquinazoline chemical series and a potential method for scaffold hopping in pursuit of new inhibitors.
authors.affiliation: Chaminade University of Honolulu, Department of Natural Sciences and Mathematics, Honolulu, HI 96816, USA. jkawakam@chaminade.edu
authors.forename: Joel K
authors.initials: JK
authors.lastname: Kawakami
authors.forename: Yannica
authors.initials: Y
authors.lastname: Martinez
authors.forename: Brandi
authors.initials: B
authors.lastname: Sasaki
authors.forename: Melissa
authors.initials: M
authors.lastname: Harris
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Kurata
authors.forename: Alan F
authors.initials: AF
authors.lastname: Lau
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D000588:Amines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D040301:Vascular Endothelial Growth Factor Receptor-2