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A combined 3D-QSAR and molecular docking strategy to understand the binding mechanism of V600EB-RAF inhibitors

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Abstract

B-RAF is a member of the RAF protein kinase family involved in the regulation of cell growth, differentiation, and proliferation. It forms a part of conserved apoptosis signals through the RAS–RAF–MAPK pathway. V600EB-RAF protein has much potential for scientific research as therapeutic target due to its involvement in human melanoma cancer. In this work, a molecular modeling study was carried out for the first time with 3D-QSAR studies by following the docking protocol on three different data sets of V600EB-RAF inhibitors. Based on the co-crystallized compound (PDB ID: 1UWJ), a receptor-guided alignment method was utilized to derive reliable CoMFA and CoMSIA models. The selected CoMFA model gives the best statistical values (q 2 = 0.753, r 2 = 0.962). With the same alignment protocol, a statistically reliable CoMSIA model out of fourteen different combinations was also derived (q 2 = 0.807, r 2 = 0.961). The actual predictive powers of both models were rigorously validated with an external test set, which gave satisfactory predictive r 2 values for CoMFA and CoMSIA models, 0.89 and 0.88, respectively. In addition, y-randomization test was also performed to validate our 3D-QSAR models. Contour maps from CoMFA and CoMSIA models supported statistical results, revealed important structural features responsible for biological activity within the active site and explained the correlation between biological activity and receptor–ligand interactions. Based on the developed models few new structures were designed. The newly predicted structure (IIIa) showed higher inhibitory potency (pIC50 6.826) than that of the most active compound of the series.

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Authors and Affiliations

  1. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan

    Zaheer Ul-Haq, Uzma Mahmood & Sauleha Reza

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  1. Zaheer Ul-Haq
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  2. Uzma Mahmood
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  3. Sauleha Reza
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Correspondence to Zaheer Ul-Haq.

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Ul-Haq, Z., Mahmood, U. & Reza, S. A combined 3D-QSAR and molecular docking strategy to understand the binding mechanism of V600EB-RAF inhibitors. Mol Divers 16, 771–785 (2012). https://doi.org/10.1007/s11030-012-9395-9

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  • DOI: https://doi.org/10.1007/s11030-012-9395-9

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