Structural Contributions of Substrates to their Binding to P-Glycoprotein. A TOPSMODE Approach
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.
Keywords: (MDRR); Automated Rule-Extraction; DEREK; MULTICASE; P-glycoprotein; P-gp Efflux; PSET; QSAR; Randi ’s method; Spectral Moments; TOPKAT; TOPS-MODE; TSET; biophore; graph-theory descriptors; knowledge generation; linear discriminant analysis (LDA); molecular modeling; natural detoxification system; orthogonalization
Document Type: Research Article
Affiliations: Department of Mathematics and Statistics, Department of Physics, Institute of Complexity Systems, University of Strathclyde Glasgow, G1 1XQ, UK.
Publication date: 2010-08-01
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