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Analysis of B-Raf\(^{\mathrm{V600E}}\) inhibitors using 2D and 3D-QSAR, molecular docking and pharmacophore studies

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Abstract

In the present work, a molecular modeling study was carried out using 2D and 3D quantitative structure-activity relationships for the various series of compounds known as B-Raf\(^{\mathrm{V600E}}\) inhibitors. For 2D-QSAR analysis, a linear model was developed by MLR based on GA-OLS with appropriate results \((Q^{2}_{\mathrm{LOO}}= 0.796, R^{2}_{\mathrm{train}}= 0.827)\), which was validated by several external validation techniques. To perform a 3D-QSAR analysis, CoMFA and CoMSIA methods were used. The selected CoMFA model could provide reliable statistical values \((Q^{2}_{\mathrm{LOO}} = 0.683, r^{2} = 0.947)\) based on the training set in the biases of the selected alignment. Using the same selected alignment, a statistically reliable CoMSIA model, out of thirty-one different combinations, was also obtained \((Q^{2}_{\mathrm{LOO}}= 0.645, r^{2} = 0.897)\). The predictive accuracy of the derived models was rigorously evaluated with the external test set of nineteen compounds based on several validation techniques. Molecular docking simulations and pharmacophore analyses were also performed to derive the true conformations of the most potent inhibitors with B-Raf\(^{\mathrm{V600E}}\) kinase.

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Acknowledgments

Reza Aalizadeh would like to thank the State Scholarships’ Foundation of Greece (I.K.Y.) for financial support.

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Authors and Affiliations

  1. Laboratory of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, P. O. Box 157 71, Athens, Greece

    Reza Aalizadeh

  2. Department of Chemistry, Payame Noor University, P. O. Box 19395-3697, Tehran, Iran

    Eslam Pourbasheer

  3. Center of Excellence in Electrochemistry, University of Tehran, Tehran, Iran

    Mohammad Reza Ganjali

  4. Biosensor Research Center, Endocrinology & Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad Reza Ganjali

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  1. Reza Aalizadeh
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Correspondence to Eslam Pourbasheer.

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Aalizadeh, R., Pourbasheer, E. & Ganjali, M.R. Analysis of B-Raf\(^{\mathrm{V600E}}\) inhibitors using 2D and 3D-QSAR, molecular docking and pharmacophore studies. Mol Divers 19, 915–930 (2015). https://doi.org/10.1007/s11030-015-9626-y

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