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Virtual Screening of Specific Insulin-Like Growth Factor 1 Receptor (IGF1R) Inhibitors from the National Cancer Institute (NCI) Molecular Database
National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China
Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun 130024, China
* Authors to whom correspondence should be addressed.
Received: 10 October 2012; in revised form: 21 November 2012 / Accepted: 11 December 2012 / Published: 14 December 2012
Abstract: Insulin-like growth factor 1 receptor (IGF1R) is an attractive drug target for cancer therapy and research on IGF1R inhibitors has had success in clinical trials. A particular challenge in the development of specific IGF1R inhibitors is interference from insulin receptor (IR), which has a nearly identical sequence. A few potent inhibitors that are selective for IGF1R have been discovered experimentally with the aid of computational methods. However, studies on the rapid identification of IGF1R-selective inhibitors using virtual screening and confidence-level inspections of ligands that show different interactions with IGF1R and IR in docking analysis are rare. In this study, we established virtual screening and binding-mode prediction workflows based on benchmark results of IGF1R and several kinase receptors with IGF1R-like structures. We used comprehensive analysis of the known complexes of IGF1R and IR with their binding ligands to screen specific IGF1R inhibitors. Using these workflows, 17 of 139,735 compounds in the NCI (National Cancer Institute) database were identified as potential specific inhibitors of IGF1R. Calculations of the potential of mean force (PMF) with GROMACS were further conducted for three of the identified compounds to assess their binding affinity differences towards IGF1R and IR.
Keywords: IGF1R; IR; virtual screening; binding mode prediction; selective inhibition
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Fan, C.; Huang, Y.-X.; Bao, Y.-L.; Sun, L.-G.; Wu, Y.; Yu, C.-L.; Zhang, Y.; Song, Z.-B.; Zheng, L.-H.; Sun, Y.; Wang, G.-N.; Li, Y.-X. Virtual Screening of Specific Insulin-Like Growth Factor 1 Receptor (IGF1R) Inhibitors from the National Cancer Institute (NCI) Molecular Database. Int. J. Mol. Sci. 2012, 13, 17185-17209.
Fan C, Huang Y-X, Bao Y-L, Sun L-G, Wu Y, Yu C-L, Zhang Y, Song Z-B, Zheng L-H, Sun Y, Wang G-N, Li Y-X. Virtual Screening of Specific Insulin-Like Growth Factor 1 Receptor (IGF1R) Inhibitors from the National Cancer Institute (NCI) Molecular Database. International Journal of Molecular Sciences. 2012; 13(12):17185-17209.
Fan, Cong; Huang, Yan-Xin; Bao, Yong-Li; Sun, Lu-Guo; Wu, Yin; Yu, Chun-Lei; Zhang, Yu; Song, Zhen-Bo; Zheng, Li-Hua; Sun, Ying; Wang, Guan-Nan; Li, Yu-Xin. 2012. "Virtual Screening of Specific Insulin-Like Growth Factor 1 Receptor (IGF1R) Inhibitors from the National Cancer Institute (NCI) Molecular Database." Int. J. Mol. Sci. 13, no. 12: 17185-17209.