title: Discovery of novel dual VEGFR2 and Src inhibitors using a multistep virtual screening approach.
abstract: Simultaneous inhibition of VEGFR2 and Src may enhance the efficacy of VEGFR2-targeted cancer therapeutics. Hence, development of dual inhibitors on VEGFR2 and Src can be a useful strategy for such treatments.
  
  
  
  A multistep virtual screening protocol, comprising ligand-based support vector machines method, drug-likeness rules filter and structure-based molecular docking, was developed and employed to identify dual inhibitors of VEGFR2 and Src from a large commercial chemical library. Kinase inhibitory assays and cell viability assays were then used for experimental validation.
  
  
  
  A set of compounds belonging to six different molecular scaffolds was identified and sent for biological evaluation. Compound 3c belonging to the 2-amino-3-cyanopyridine scaffold exhibited good antiproliferative effect and dual-target activities against VEGFR2 and Src.
  
  
  
  This study demonstrated the ability of the multistep virtual screening approach to identify novel multitarget agents.
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Shangying
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Chu
authors.initials: C
authors.lastname: Qin
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Jia En
authors.initials: JE
authors.lastname: Sin
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Xuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Lin
authors.initials: L
authors.lastname: Tao
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Xian
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Shenzhen Kivita Innovative Drug Discovery Institute & the Key Laboratory of Chemical Biology, Guangdong Province, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong, PR China.
authors.forename: Chun Mei
authors.initials: CM
authors.lastname: Gao
authors.affiliation: Shenzhen Kivita Innovative Drug Discovery Institute & the Key Laboratory of Chemical Biology, Guangdong Province, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong, PR China.
authors.forename: Yu Yang
authors.initials: YY
authors.lastname: Jiang
authors.affiliation: Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55902, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Yu Zong
authors.initials: YZ
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Wai Keung
authors.initials: WK
authors.lastname: Chui
mesh_terms: D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases
keywords: 2-amino-3-cyanopyridines; Src; Surflex–Dock; VEGFR2; cancer; combinatorial support vector machines; drug discovery; molecular docking; multikinase inhibitors; virtual screening