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Pharmacophore modeling, 3D-QSAR, and molecular docking study on naphthyridine derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase-1

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Abstract

The 3-phosphoinositide-dependent protein kinase-1 (PDK1) is an imminent target for discovering novel anticancer drugs. In order to understand the structure–activity correlation of naphthyridine-based PDK-1 inhibitors, we have carried out a combined pharmacophore, three-dimensional quantitative structure–activity relationship (3D-QSAR), and molecular docking studies. The study has resulted in six point pharmacophore models with four hydrogen bond acceptors (A), one hydrogen bond donor (D), and one aromatic ring (R) are used to derive a predictive atom-based 3D-QSAR model. The generated 3D-QSAR model shows that the alignment has good correlation coefficient for the training set compounds which comprises the values of R 2 = 0.96, SD = 0.2, and F = 198.2. Test set compounds shows Q 2 = 0.84, RMSE = 0.56, and Pearson-R = 0.84. The external validation was carried out to validate the predicted QSAR model which shows good predictive power of \( r_{m}^{2} \) = 0.83 and k = 1.01, respectively. The external validation results also confirm the fitness of the model. The results indicated that, atom-based 3D-QSAR models and further modifications in PDK1 inhibitors via pharmacophore hypothesis are rational for the prediction of the activity of new inhibitors in prospect of drug design.

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Correspondence to Karthikeyan Muthusamy.

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Kirubakaran, P., Muthusamy, K., Dhanachandra Singh, K. et al. Pharmacophore modeling, 3D-QSAR, and molecular docking study on naphthyridine derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase-1. Med Chem Res 22, 3812–3822 (2013). https://doi.org/10.1007/s00044-012-0383-5

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Keywords

  • 3-Phosphoinositide-dependent protein kinase-1; PDK1
  • Pharmacophore mapping
  • 3D-QSAR
  • External validation
  • Molecular docking