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Vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors: development and validation of predictive 3-D QSAR models through extensive ligand- and structure-based approaches

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Abstract

Vascular endothelial growth factor receptor-2, (VEGFR-2), is a key element in angiogenesis, the process by which new blood vessels are formed, and is thus an important pharmaceutical target. Here, 3-D quantitative structure–activity relationship (3-D QSAR) were used to build a quantitative screening and pharmacophore model of the VEGFR-2 receptors for design of inhibitors with improved activities. Most of available experimental data information has been used as training set to derive optimized and fully cross-validated eight mono-probe and a multi-probe quantitative models. Notable is the use of 262 molecules, aligned following both structure-based and ligand-based protocols, as external test set confirming the 3-D QSAR models’ predictive capability and their usefulness in design new VEGFR-2 inhibitors. From a survey on literature, this is the first generation of a wide-ranging computational medicinal chemistry application on VEGFR2 inhibitors.

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Acknowledgments

E.P. thanks MESR for Ph.D. grant.

Funding

This study was funded by Italian Minister of University and Research (MIUR) (PRIN Grant. 20105YY2HL_003 and FIRB Grant RBFR10ZJQT).

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Authors and Affiliations

  1. Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P. le A. Moro 5, 00185, Rome, Italy

    Rino Ragno, Flavio Ballante, Adele Pirolli & Alexandros Patsilinakos

  2. Magma Dynamics srl, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P. le A. Moro 5, 00185, Rome, Italy

    Rino Ragno & Alexandros Patsilinakos

  3. Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis School of Medicine, 700 South Euclid Avenue, St. Louis, MO, 63110, USA

    Flavio Ballante & Richard B. Wickersham III

  4. SRSMC UMR CNRS7565 (former LIMBP), 1 Boulevard Arago, 57070, Metz, France

    Stéphanie Hesse, Enrico Perspicace & Gilbert Kirsch

  5. Genfit, Parc Eurasanté, 885 Avenue Eugène Avinée, 59120, Loss, France

    Enrico Perspicace

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  1. Rino Ragno
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Ragno, R., Ballante, F., Pirolli, A. et al. Vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors: development and validation of predictive 3-D QSAR models through extensive ligand- and structure-based approaches. J Comput Aided Mol Des 29, 757–776 (2015). https://doi.org/10.1007/s10822-015-9859-y

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  • DOI: https://doi.org/10.1007/s10822-015-9859-y

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