Shangying Chen1, Chu Qin1, Jia En Sin1, Xuan Yang1, Lin Tao1, Xian Zeng1, Peng Zhang1, Chun Mei Gao2, Yu Yang Jiang2, Cheng Zhang3, Yu Zong Chen1, Wai Keung Chui1. 1. Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543. 2. 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. 3. Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55902, USA.
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. Compound 3c 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.
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. Compound 3c 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.
Entities:
Keywords:
2-amino-3-cyanopyridines; Src; Surflex–Dock; VEGFR2; cancer; combinatorial support vector machines; drug discovery; molecular docking; multikinase inhibitors; virtual screening