Dataset Information

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

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.

SUBMITTER: Jain S

PROVIDER: S-EPMC6422297 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Jain Sankalp S Grandits Melanie M Ecker Gerhard F GF

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 20180622

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 ...[more]

PMID: 29936088

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Project description:BackgroundBark beetles are major pests of conifer forests, and their behavior is primarily mediated via olfaction. Targeting the odorant receptors (ORs) may thus provide avenues towards improved pest control. Such an approach requires information on the function of ORs and their interactions with ligands, which is also essential for understanding the functional evolution of these receptors. Hence, we aimed to identify a high-quality complement of ORs from the destructive spruce bark beetle Ips typographus (Coleoptera, Curculionidae, Scolytinae) and analyze their antennal expression and phylogenetic relationships with ORs from other beetles. Using 68 biologically relevant test compounds, we next aimed to functionally characterize ecologically important ORs, using two systems for heterologous expression. Our final aim was to gain insight into the ligand-OR interaction of the functionally characterized ORs, using a combination of computational and experimental methods.ResultsWe annotated 73 ORs from an antennal transcriptome of I. typographus and report the functional characterization of two ORs (ItypOR46 and ItypOR49), which are responsive to single enantiomers of the common bark beetle pheromone compounds ipsenol and ipsdienol, respectively. Their responses and antennal expression correlate with the specificities, localizations, and/or abundances of olfactory sensory neurons detecting these enantiomers. We use homology modeling and molecular docking to predict their binding sites. Our models reveal a likely binding cleft lined with residues that previously have been shown to affect the responses of insect ORs. Within this cleft, the active ligands are predicted to specifically interact with residues Tyr84 and Thr205 in ItypOR46. The suggested importance of these residues in the activation by ipsenol is experimentally supported through site-directed mutagenesis and functional testing, and hydrogen bonding appears key in pheromone binding.ConclusionsThe emerging insight into ligand binding in the two characterized ItypORs has a general importance for our understanding of the molecular and functional evolution of the insect OR gene family. Due to the ecological importance of the characterized receptors and widespread use of ipsenol and ipsdienol in bark beetle chemical communication, these ORs should be evaluated for their potential use in pest control and biosensors to detect bark beetle infestations.

Project description:In present, interspecies cloning and interspecies-pregnancy were studied for endangered species rescue. However, the low implantation and survival ratio, spontaneous abortion, and unknown reason embryos absorption are the common and difficult problems of interspecies-pregnancy. In order to discover the mechanism of interspecies-pregnant failure and find ways to overcome the xeon-pregnant obstacles, we chosen the rat embryos pregnant in mouse uterus as a interspecies-pregnancy model. Three groups were set, mouse embryos to mouse recipients (MM) as control group, rat embryos to mouse recipients (RM), and rat and mouse embryos to mouse recipients together (RMM) as experiment groups. The former studies showed that rat embryos live no longer than day 7 of mouse pregnancy (D7). Our results showed that rat embryos survived to D7, and still existed to day 9 of mouse pregnancy (D9) in RM group. Surprisingly, the rat embryos survived to day 13 of the mouse gestation (D13) in RMM group. Microarray analysis was used to detect the global-gene expression profile changes of the whole implantation sites among the three groups at D7 and D9. By this way, we screened out the genes promoting the implanted rat embryos development in a mouse uterus which helped the rat embryos survive to D13 in RMM group compared with RM group, and the genes hindering the rat embryos development in a mouse uterus which prevented rat embryos living longer than D7 in RM group and D13 in RMM group compared with MM group. These findings provide insights into the mechanism of interspecies pregnant failure and new idea for interspecies pregnant studies. Experiment Overall Design: microarray was use to screen the genes among the day 7 and day 9 implantation sites of rat embryos implantation sites in a mouse uterus between rat embryos transfer to mouse recipients and rat embryos transfer to mouse recipients with mouse embryos. The mouse day7 and day 9 embryos implantation sites were use as control. Experiment Overall Design: totally 6 samples were analyzed, each samples two replications (one of them had three replications).

Dataset Information

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

Publications

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

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