Abstract
A series of indole-based C-3 pyridone compounds active against Hepatitis C virus as HCV NS5B polymerase inhibitors have been explored under the framework of quantitative structure–activity relationships (QSARs) and pharmacophore modeling in the present article. QSAR models were developed by considering various kinds of theoretical molecular descriptors including constitutional and geometrical, topological, functional group, and atom-centered fragments indices computed solely from the structure of indole-based C-3 pyridone compounds utilizing stepwise forward−backward variable selections incorporated in multiple linear regression (MLR) methods. MLR shows that topological indices can contribute the maximum impact on biological activity obtained in terms of model quality parameters, such as R 2 = 0.946, \( Q_{\text{Loo}}^{2} \) = 0.883, and \( R_{\text{pred}}^{2} \) = 0.642, respectively. Constitutional and geometrical-based model can produce R 2 = 0.849, \( Q_{\text{Loo}}^{2} \) = 0.776, and \( R_{\text{pred}}^{2} \) = 0.623, respectively; whereas, model utilizing functional group and atom-centered fragments indices can contribute R 2 = 0.885, \( Q_{\text{Loo}}^{2} \) = 0.812, and \( R_{\text{pred}}^{2} \) = 0.612, respectively. Prediction of essential structural features is strongly achieved by introducing pharmacophore modeling of these highly active congeners which showed that more number of hydrogen bonding interactions between the substituents associated to the various points of diversity of the indole nucleus including N-1, C-2, and C-3 aromatic groups with the HCV NS5B polymerase target may enhance the biological activities in this congeneric ligands.
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Acknowledgments
Authors are sincerely thankful to their corresponding Institute for providing necessary research facilities. Ankita shows deep sense of gratitude to her supervisor Dr. Nandi for his excellent guidance. MCB acknowledges the Council of Scientific and Industrial Research (CSIR), New Delhi, India for the Grant of a CSIR Emeritus Scientist award to him. SN is thankful to National Institute of Chemistry Slovenia for availing DRAGON Professional version 5.4-2006 software for the calculation of theoretical molecular descriptors and LIGANDSCOUT 2.02 software for pharmacophore modeling used in the present work.
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Batra, A., Nandi, S. & Bagchi, M.C. QSAR and pharmacophore modeling of indole-based C-3 pyridone compounds as HCV NS5B polymerase inhibitors utilizing computed molecular descriptors. Med Chem Res 24, 2432–2440 (2015). https://doi.org/10.1007/s00044-014-1304-6
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DOI: https://doi.org/10.1007/s00044-014-1304-6