Docking and quantitative structure–activity relationship of oxadiazole derivates as inhibitors of GSK3\(\upbeta \)

Abstract

The binding modes of 42 oxadiazole derivates inside glycogen synthase kinase 3 beta (GSK3\(\upbeta )\) were determined using docking experiments; thus, the preferred active conformations of these inhibitors are proposed. We found that these compounds adopt a scorpion-shaped conformation and they accept a hydrogen bond (HB) from the residue Val135 of the GSK3\(\upbeta \) ATP-binding site hinge region. In addition, quantitative structure–activity relationship (QSAR) models were constructed to explain the trend of the GSK3\(\upbeta \) inhibitory activities for the studied compounds. In a first approach, three-dimensional (3D) vectors were calculated using docking conformations and, by using multiple-linear regression, we assessed that GETAWAY vectors were able to describe the reported biological activities. In other QSAR approach, SMILES-based optimal descriptors were calculated. The best model included three-SMILES elements SSS\(_\mathrm{k}\) leading to the identification of key molecular features that contribute to a high GSK3\(\upbeta \) inhibitory activity.

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Acknowledgments

This study was supported by FONDECYT Regular # 1130141. Authors would like to express their sincere gratitude to Editor in Chief Guillermo A. Morales for assistance with the English correction of the manuscript.

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Correspondence to Julio Caballero.

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Quesada-Romero, L., Caballero, J. Docking and quantitative structure–activity relationship of oxadiazole derivates as inhibitors of GSK3\(\upbeta \) . Mol Divers 18, 149–159 (2014). https://doi.org/10.1007/s11030-013-9483-5

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Keywords

  • GSK3\(\upbeta \) inhibitors
  • Oxadiazole derivates
  • Docking
  • Quantitative structure–activity relationships
  • Three-dimensional descriptors
  • Optimal descriptors