Ernesto Estrada, Enrique Molina, Delvin Nodarse and Eugenio Uriarte Pages 2676 - 2709 ( 34 )
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.
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
, , , Department of Mathematics and Statistics, Department of Physics, Institute of Complexity Systems, University of Strathclyde Glasgow, G1 1XQ, UK.