Docking and quantitative structure-activity relationship studies for 3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)aniline, 3-fluoro-4-(1H- pyrrolo[2,3-b]pyridin-4-yloxy)aniline, and 4-(4-amino-2-fluorophenoxy)-2- pyridinylamine derivatives as c-Met kinase inhibitors

Julio Caballero, Miguel Quiliano, Jans H. Alzate-Morales, Mirko Zimic, Eric Deharo

Research output: Contribution to journalArticlepeer-review

Abstract

We have performed docking of 3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4- yloxy)aniline (FPTA), 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (FPPA), and 4-(4-amino-2-fluorophenoxy)-2-pyridinylamine (AFPP) derivatives complexed with c-Met kinase to study the orientations and preferred active conformations of these inhibitors. The study was conducted on a selected set of 103 compounds with variations both in structure and activity. Docking helped to analyze the molecular features which contribute to a high inhibitory activity for the studied compounds. In addition, the predicted biological activities of the c-Met kinase inhibitors, measured as IC50 values were obtained by using quantitative structure-activity relationship (QSAR) methods: Comparative molecular similarity analysis (CoMSIA) and multiple linear regression (MLR) with topological vectors. The best CoMSIA model included steric, electrostatic, hydrophobic, and hydrogen bond-donor fields; furthermore, we found a predictive model containing 2D-autocorrelation descriptors, GETAWAY descriptors (GETAWAY: Geometry, Topology and Atom-Weight AssemblY), fragment-based polar surface area (PSA), and MlogP. The statistical parameters: cross-validate correlation coefficient and the fitted correlation coefficient, validated the quality of the obtained predictive models for 76 compounds. Additionally, these models predicted adequately 25 compounds that were not included in the training set.

Original languageEnglish (US)
Pages (from-to)349-369
Number of pages21
JournalJournal of Computer-Aided Molecular Design
Volume25
Issue number4
DOIs
StatePublished - Apr 2011

Keywords

  • CoMSIA
  • Molecular docking
  • Quantitative structure-activity relationships
  • Topological descriptors
  • c-Met kinase inhibitors

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry

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