Structural contributions of substrates to their binding to P-Glycoprotein. A TOPS-MODE approach

Ernesto Estrada, Enrique Molina, Delvin Nodarse, Eugenio Uriarte

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A topological substructural molecular design approach (TOPS-MODE) has been used to formulate structural rules for binding of substrates of P-glycoprotein (P-gp). We first review some of the models developed in the recent literature for predicting binding to Pgp. Then, we develop a model using TOPS-MODE, which is able to identify 88.4% of substrates and 84.2% of non-substrates. When the model is presented to an external prediction set of 100 substrates and 77 nonsubstrates it identifies correctly 81.8% of all cases. Using TOPS-MODE strategy we found structural contributions for binding to P-gp, which identifies 24 structural fragments responsible for such binding. We then carried out a chemico-biological analysis of some of the structural fragments found as contributing to P-gp binding of substrates. We show that in general the model developed so far can be used as a virtual screening method for identifying substrates of P-gp from large libraries of compounds.
Original languageEnglish
Pages (from-to)2676-2709
Number of pages33
JournalCurrent Pharmaceutical Design
Issue number24
Publication statusPublished - Aug 2010


  • knowledge generation
  • P-glycoprotein
  • QSAR
  • molecular modeling
  • Spectral Moments
  • graph-theory descriptors
  • natural detoxification system
  • (MDRR)
  • linear discriminant analysis (LDA)
  • Automated Rule-Extraction
  • Randi 's method
  • biophore
  • TSET
  • PSET
  • P-gp Efflux
  • orthogonalization

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