title: Structural contributions of substrates to their binding to P-Glycoprotein. A TOPS-MODE 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 P-gp. 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.
authors.affiliation: Department of Mathematics and Statistics, Institute of Complexity Systems, University of Strathclyde Glasgow, UK. ernesto.estrada@strath.ac.uk
authors.forename: Ernesto
authors.initials: E
authors.lastname: Estrada
authors.forename: Enrique
authors.initials: E
authors.lastname: Molina
authors.forename: Delvin
authors.initials: D
authors.lastname: Nodarse
authors.forename: Eugenio
authors.initials: E
authors.lastname: Uriarte
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D051379:Mice; D008954:Models, Biological; D015394:Molecular Structure; D011485:Protein Binding; D021381:Protein Transport; D021281:Quantitative Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1