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

Ernesto Estrada, Enrique Molina, Delvin Nodarse, Eugenio Uriarte

Research output: Contribution to journalArticle

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Abstract

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.
LanguageEnglish
Pages2676-2709
Number of pages33
JournalCurrent Pharmaceutical Design
Volume16
Issue number24
Publication statusPublished - Aug 2010

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P-Glycoprotein

Keywords

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

Cite this

Estrada, E., Molina, E., Nodarse, D., & Uriarte, E. (2010). Structural contributions of substrates to their binding to P-Glycoprotein. A TOPS-MODE approach. Current Pharmaceutical Design, 16(24), 2676-2709.
Estrada, Ernesto ; Molina, Enrique ; Nodarse, Delvin ; Uriarte, Eugenio. / Structural contributions of substrates to their binding to P-Glycoprotein. A TOPS-MODE approach. In: Current Pharmaceutical Design. 2010 ; Vol. 16, No. 24. pp. 2676-2709.
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Estrada, E, Molina, E, Nodarse, D & Uriarte, E 2010, 'Structural contributions of substrates to their binding to P-Glycoprotein. A TOPS-MODE approach' Current Pharmaceutical Design, vol. 16, no. 24, pp. 2676-2709.

Structural contributions of substrates to their binding to P-Glycoprotein. A TOPS-MODE approach. / Estrada, Ernesto; Molina, Enrique; Nodarse, Delvin; Uriarte, Eugenio.

In: Current Pharmaceutical Design, Vol. 16, No. 24, 08.2010, p. 2676-2709.

Research output: Contribution to journalArticle

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