Interspecies comparison of putative ligand binding sites of human, rat and mouse P-glycoprotein

Author(s)
Sankalp Jain, Melanie Grandits, Gerhard F Ecker
Abstract

Prior to the clinical phases of testing, safety, efficacy and pharmacokinetic profiles of lead compounds are evaluated in animal studies. These tests are primarily performed in rodents, such as mouse and rats. In order to reduce the number of animal experiments, computational models that predict the outcome of these studies and thus aid in prioritization of preclinical candidates are heavily needed. However, although computational models for human off-target interactions with decent quality are available, they cannot easily be transferred to rodents due to lack of respective data. In this study, we assess the transferability of human P-glycoprotein activity data for development of in silico models to predict in vivo effects in rats and mouse using a structure-based approach. P-glycoprotein (P-gp) is an ATP-dependent efflux transporter that transports xenobiotic compounds such as toxins and drugs out of cells and has a broad substrate and inhibitor specificity. Being mostly expressed at barriers, it influences the bioavailability of drugs and thus contributes also to toxicity. Comparison of the binding site interaction profiles of human, rat and mouse P-gp derived from docking studies with a set of common inhibitors suggests that the inhibitors share potentially similar binding modes. These findings encourage the use of in vitro human P-gp data for predicting in vivo effects in rodents and thus contributes to the 3Rs (Replace, Reduce and Refine) of animal experiments.

Organisation(s)
Journal
European Journal of Pharmaceutical Sciences
Volume
122
Pages
134-143
No. of pages
10
ISSN
0928-0987
DOI
https://doi.org/10.1016/j.ejps.2018.06.022
Publication date
06-2018
Peer reviewed
Yes
Austrian Fields of Science 2012
301207 Pharmaceutical chemistry
Keywords
ASJC Scopus subject areas
Pharmaceutical Science
Portal url
https://ucris.univie.ac.at/portal/en/publications/interspecies-comparison-of-putative-ligand-binding-sites-of-human-rat-and-mouse-pglycoprotein(9bc0d95b-00c8-44f7-b0ba-e4a05c1f30f6).html