Structural Contributions of Substrates to their Binding to P-Glycoprotein. A TOPSMODE Approach
Authors: Estrada, Ernesto; Molina, Enrique; Nodarse, Delvin; Uriarte, Eugenio
Source: Current Pharmaceutical Design, Volume 16, Number 24, August 2010 , pp. 2676-2709(34)
Publisher: Bentham Science Publishers
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: August 1, 2010
- Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.
Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.