Development of in silico filters to predict activation of the pregnane X receptor (PXR) by structurally diverse drug-like molecules

Bioorganic & Medicinal Chemistry
Hans MatterKarl-Heinz Baringhaus

Abstract

The pregnane X receptor (PXR), a member of the nuclear hormone superfamily, regulates the expression of several enzymes and transporters involved in metabolically relevant processes. The significant induction of CYP450 enzymes by PXR, in particular CYP3A4, might significantly alter the metabolism of prescribed drugs. In order to early identify molecules in drug discovery with a potential to activate PXR as antitarget, we developed fast and reliable in silico filters by ligand-based QSAR techniques. Two classification models were established on a diverse dataset of 434 drug-like molecules. A second augmented set allowed focusing on interesting regions in chemical space. These classifiers are based on decision trees combined with a genetic algorithm based variable selection to arrive at predictive models. The classifier for the first dataset on 29 descriptors showed good performance on a test set with a correct classification of both 100% for PXR activators and non-activators plus 87% for activators and 83% for non-activators in an external dataset. The second classifier then correctly predicts 97% activators and 91% non-activators in a test set and 94% for activators and 64% non-activators in an external set of 50 molecules, whi...Continue Reading

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Citations

Mar 1, 2014·Future Medicinal Chemistry·Friedemann SchmidtAndreas Czich
Feb 26, 2016·Chemical Research in Toxicology·Denis MullinerAlexander Amberg
Dec 3, 2014·Drug Discovery Today·Monimoy BanerjeeTaosheng Chen
Jul 5, 2016·Journal of Huazhong University of Science and Technology. Medical Sciences = Hua Zhong Ke Ji Da Xue Xue Bao. Yi Xue Ying De Wen Ban = Huazhong Keji Daxue Xuebao. Yixue Yingdewen Ban·Yi-Ming ZhangXiao Han
Sep 8, 2016·Chemical Research in Toxicology·Mohamed Diwan M AbdulHameedAnders Wallqvist
Aug 20, 2014·Journal of Chemical Information and Modeling·Lennart T AngerSebastian G Rohrer
Aug 14, 2015·International Journal of Toxicology·Tiong Chai SeahMei Lan Tan
Oct 12, 2018·Toxicology Mechanisms and Methods·Guangyao HuangYue Gao
Jul 13, 2017·Environmental Science and Pollution Research International·Cen YinHuihui Liu
Jan 8, 2019·Journal of Chemical Information and Modeling·Jan WenzelFriedemann Schmidt
Mar 7, 2020·Journal of Medicinal Chemistry·Christoph GrebnerGerhard Hessler

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