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.
Highlights
The efflux transporter P-glycoprotein (P-gp) is a protein of high interest among other major anti-targets (Cramer et al, 2007)
In order to reduce the number of animal experiments, computational models that predict the outcome of these studies and aid in prioritization of preclinical candidates are heavily needed
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
Summary
The efflux transporter P-glycoprotein (P-gp) is a protein of high interest among other major anti-targets (Cramer et al, 2007) It is expressed in tissues such as intestine, liver, kidney, placenta, testis, and in the capillary endothelial cells of the brain (Seelig, 1998; Thiebaut et al, 1987), and plays an important role in the absorption, distribution and excretion of many drugs. Concomitant administration of substrates and P-gp inhibitors may lead to adverse drug reactions and organ toxicities (Balayssac et al, 2005). Computational methods that characterize P-gp interactions and guide the prioritization of compounds in the early phase of the drug discovery process are of considerable interest (Schneider, 2010)
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