Combined 3D-QSAR modeling and molecular docking study on indolinone derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase-1

Mohamed Diwan M. Abdulhameed, Adel Hamza, Junjun Liu, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

3-Phosphoinositide-dependent protein kinase-1 (PDK1) is a promising target for developing novel anticancer drugs. In order to understand the structure-activity correlation of indolinone-based PDK1 inhibitors, we have carried out a combined molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling study. The study has resulted in two types of satisfactory 3D-QSAR models, including the CoMFA model (r 2 = 0.907; q2 = 0.737) and CoMSIA model (r2 = 0.991; q2 = 0.824), for predicting the biological activity of new compounds. The detailed microscopic structures of PDK1 binding with inhibitors have been studied by molecular docking. We have also developed docking-based 3D-QSAR models (CoMFA with q2 = 0.729; CoMSIA with q2 = 0.79). The contour maps obtained from the 3D-QSAR models in combination with the docked binding structures help to better interpret the structure-activity relationship. All of the structural insights obtained from both the 3D-QSAR contour maps and molecular docking are consistent with the available experimental activity data. This is the first report on 3D-QSAR modeling of PDK1 inhibitors. The satisfactory results strongly suggest that the developed 3D-QSAR models and the obtained PDK1-inhibitor binding structures are reasonable for the prediction of the activity of new inhibitors and in future drug design.

Original languageEnglish
Pages (from-to)1760-1772
Number of pages13
JournalJournal of Chemical Information and Modeling
Volume48
Issue number9
DOIs
StatePublished - Sep 2008

ASJC Scopus subject areas

  • General Chemistry
  • General Chemical Engineering
  • Computer Science Applications
  • Library and Information Sciences

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