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.
|Number of pages||33|
|Journal||Current Pharmaceutical Design|
|Publication status||Published - Aug 2010|
- knowledge generation
- molecular modeling
- Spectral Moments
- graph-theory descriptors
- natural detoxification system
- linear discriminant analysis (LDA)
- Automated Rule-Extraction
- Randi 's method
- P-gp Efflux
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.