Using the Variable-Nearest Neighbor Method To Identify P-Glycoprotein Substrates and Inhibitors

ACS Omega
Patric SchymanAnders Wallqvist

Abstract

Permeability glycoprotein (Pgp) is an essential membrane-bound transporter that efficiently extracts compounds from a cell. As such, it is a critical determinant of the pharmacokinetic properties of drugs. Multidrug resistance in cancer is often associated with overexpression of Pgp, which increases the efflux of chemotherapeutic agents from the cell. This, in turn, may prevent an effective treatment by reducing the effective intracellular concentrations of such agents. Consequently, identifying compounds that can either be transported out of the cell by Pgp (substrates) or impair Pgp function (inhibitors) is of great interest. Herein, using publically available data, we developed quantitative structure-activity relationship (QSAR) models of Pgp substrates and inhibitors. These models employed a variable-nearest neighbor (v-NN) method that calculated the structural similarity between molecules and hence possessed an applicability domain, that is, they used all nearest neighbors that met a minimum similarity constraint. The performance characteristics of these v-NN-based models were comparable or at times superior to those of other model constructs. The best v-NN models for identifying either Pgp substrates or inhibitors showed ...Continue Reading

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Citations

Dec 20, 2017·Frontiers in Pharmacology·Patric SchymanAnders Wallqvist
Aug 11, 2017·Journal of Chemical Information and Modeling·Ruifeng LiuAnders Wallqvist

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Methods Mentioned

BETA
in silico methods

Software Mentioned

FLAP
Accelrys
GOLD
VolSurf

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