Discovery of novel dual VEGFR2 and Src inhibitors using a multistep virtual screening approach. (January 2017)

• Record Type: Journal Article
• Authors: Chen, Shangying; Qin, Chu; Sin, Jia En; Yang, Xuan; Tao, Lin; Zeng, Xian; Zhang, Peng; Gao, Chun Mei; Jiang, Yu Yang; Zhang, Cheng; Chen, Yu Zong; Chui, Wai Keung
• Is Part Of: Future medicinal chemistry. Volume 9:Number 1(2017)
• Page Start: 7
• Page End: 24
• Publication Date: 2017-01
• Subjects: 2-amino-3-cyanopyridines -- cancer -- combinatorial support vector machines -- drug discovery -- molecular docking -- multikinase inhibitors -- Src -- Surflex–Dock -- VEGFR2 -- virtual screening; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.4155/fmc-2016-0162
• Languages: English
• ISSNs: 1756-8919

Abstract

Aim: 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.Materials & methods: 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.Results: A set of compounds belonging to six different molecular scaffolds was identified and sent for biological evaluation. Compound3c belonging to the 2-amino-3-cyanopyridine scaffold exhibited good antiproliferative effect and dual-target activities against VEGFR2 and Src.Conclusion: This study demonstrated the ability of the multistep virtual screening approach to identify novel multitarget agents.