First, substrates partition into the membrane and enter the pgp sbd. Classification of pglycoproteininteracting compounds. Gps, as part of the newly formed clinical commissioning groups ccgs, are responsible for controlling the majority of nhs budget and will decide how and where to spend money allocated to them to meet the needs of the local healthcare economy in which they operate. Tho role of pglycoprotein in the transport of mk467. The aim of this in vitro study was to determine whether mk467 is a substrate of pgp.
Methods selection of substrates and nonsubstrates of pgp. Here we present pgprules, an online p gp substrate and p gp inhibitor prediction server with ruled. Output is a knime data table facilitating saving to a file or database, or using the predictions as inputs to subsequent workflow steps. Predicts key toxicity parameters ames mutagenicity, rat acute dose ld 50 following iv or po administration and aqueous solubility directly from structure no in vitro physicochemical or toxicity data required save money and time by allowing toxicity to be assessed virtually no synthesis required. Drugs that are substrates of pgp are subject to low intestinal. P gp is a transmembrane protein with two nucleotide atp binding domains nbd in its cytoplasmic region and a helix bundle to form a substrate binding domain sbd in its transmembrane region 2. Pgp is a transmembrane protein with two nucleotide atp binding domains nbd in its cytoplasmic region and a helix bundle to form a substrate binding domain sbd in its transmembrane region 2.
Analogs of the lignan pinoresinol as novel lead compounds. P gp substrates can be easily pumped out of the cells to reduce their absorption. We built a comprehensive dataset of binders and nonbinders based on a. Pgp influences the pharmacokinetics of its substrate drugs due to its. Pgp substrates are mainly hydrophobic and weakly amphipathic. P glycoprotein p gp functions as a drug efflux pump, mediating multidrug resistance and limiting the efficacy of many drugs. The mechanism of action of pgp is analogous to a molecular vacuum cleaner 1. In a previous study, using a similar data set the databases share over 80%. Start studying pglycoprotein substrates, inducers, and inhibitors. Annotating human pglycoprotein bioassay data ncbi nih. In this study, we developed a simplified in vitro screening method to evaluate p gp substrates by unidirectional membrane transport in p gp overexpressing cells.
The inhibition of pgp has become a notable strategy for combating multidrugresistant cancers and improving therapeutic outcomes. Full text peripheral opioid receptor antagonists for. Mk467 may be suitable for use in dogs homozygous negative for the p gp mutation. If the correlation coefficient between the pgp modulator category substrate or inhibitor and a certain descriptor was below 0.
In studies where inhibition of pgp, mrp1, mrp2 or bcrp were performed in conjunction with known substrates, cells were preincubated in hbss containing the inhibitors for 30 min before initiation of the study. An in vitro evaluation of guanfacine as a substrate for p. Pglycoprotein pgp is a polyspecific atpdependent transporter linked to multidrug resistance in cancer. At present, publicly available, reliable in silico models predicting p gp substrates are scarce. Elucidation of these interaction points and recent docking studies suggest that most of them are located in the main binding. Conversely, if the activity is similar, it suggests that p gp did not interfere with the compound, so it is likely a p gp non substrate. Using a known p gp substrate digoxin, the downregulated p gp function by the mdr1asirna was further confirmed with 60% reduction noted in the total body clearance cl of the substrate. Coadministration of paclitaxel and another drug that inhibits p gp may enhance the therapeutic effectiveness of paclitaxel by preventing its efflux from tumor cells. Nov 21, 2017 drug resistance mediated by p glycoprotein p gp renders many cancer therapies ineffective.
The pglycoprotein pgp inhibitor, verapamil, can be included to identify whether active efflux is mediated by pgp alternatively for definitive p. Pglycoprotein pgp is a transporter of great clinical and pharmacological significance. Drugs that are substrates of pgp are subject to low intestinal absorption. Mk467 may be the substrate to active cellular transport but it does not appear to be a substrate of pgp. First, substrates partition into the membrane and enter the p gp sbd. Toxicity prediction directly from chemical structure. Pglycoprotein mediated efflux limits substrate and drug uptake in a preclinical brain metastases of breast cancer model chris e.
The database is a compilation of chemical structures gathered from different. This ensures that all system tables are properly populated with the company information. It counteracts the cardiovascular and endocrine effects of the. Human pglycoprotein pgp, gene symbol abcb1 is a large polytopic membrane protein belonging to the atpbinding cassette abc multidrug transporter superfamily. There is no single experimental method to conclusively identify a compound as a substrate for pgp. Our data show that colchicine, a known pgp substrate,,, increased pgp expression in caco2 cells without a concomitant increase in the activity of the protein. The mechanism of action of p gp is analogous to a molecular vacuum cleaner 1. It assists users in the design of antitumor drug candidates to safeguard them against pgp activity seems timely, given the recent biological research on cancer stem cells. Learn vocabulary, terms, and more with flashcards, games, and other study tools. Cyp3a4 substrates, and digoxin specific pgp substrate have been established. Biozyne pgp predictor employs a support vector machine svm classifier with the radial basis function rbf kernel. Intracellular accumulation of guanfacine was compared between p gp expressing llcpk1mdr1 cells and p gp negative llcpk1 cells to evaluate the potential interaction between p gp and guanfacine. Pgp mediates efflux of a wide range of xenobiotics and endogenous compounds out of cells utilizing atp hydrolysis as the source of energy for substrate translocation.
P gp substrates were collected from the literature such that each compound has been either described as being transported by p gp or reported to induce overexpression of p gp which directly contributes to mdr. High levels of expression of pglycoprotein multidrug. Selectivity profiling of bcrp versus pgp inhibition. Conversely, if the activity is similar, it suggests that pgp did not interfere with the compound, so it is likely a pgp nonsubstrate. Pglycoprotein pgp is an efflux transporter present within the bloodbrain barrier. For efficient drug discovery and screening, it is necessary to simplify p glycoprotein p gp substrate assays and to provide in silico models that predict the transport potential of p gp.
Several structural studies of pgp and its homologs have provided insights into its transport cycle, but questions remain regarding how pgp recognizes diverse substrates and how substrate binding is. In this study, a support vector machine svm method was developed to predict p gp substrates and p gp substrate interactions, based on a training data set of 197 known p gp substrates and nonsubstrates collected from the literature. Our data is collected by our team of petroleum information analysts from a range of industry sources, providing accurate and uptodate permit, well and company data for. Novel features in the structure of pglycoprotein abcb1.
Western blot analysis of pglycoprotein was performed by separating 30 g of whole cell extract by 5% sdspage. M, also showed significantly more favorable effective binding energies than the inactive. Multiple transportactive binding sites are available for a single. We performed an in vitro study to determine if guanfacine is indeed a substrate of p gp. P glycoprotein pgp is a drug transporter that plays important roles in multidrug resistance and drug pharmacokinetics. The homology modeling of human pgp and substrate and modulator. Frontiers novel 3,4dihydroisocoumarins inhibit human p. The biozyne p gp server uses a support vector machine classifier to predict, with high accuracy, whether a compound is likely to be a substrate of the p gp drug efflux pump. Accurate models for pgp drug recognition induced from a. Moreover, the server outputs the results of simple, interpretable decision tree models, as well as highlighting effluxophores, molecular fragments that enhance or abolish. Mdr1 cell test system in which human pgp is expressed in isolation and unlike caco. Frontiers novel 3,4dihydroisocoumarins inhibit human pgp.
P glycoprotein p gp is a polyspecific atpdependent transporter linked to multidrug resistance in cancer. In fact, the observed results revealed that this pgp substrate is able to significantly induce pgp expression in a concentration dependent manner, up to 183% for the highest. Understanding the structural basis of p gp, substrate polyspecificity has been hampered by its intrinsic flexibility, which is facilitated by a 75residue linker. Pgp substrates were collected from the literature such that each compound has been either described as being transported by pgp or reported to induce overexpression of pgp which directly contributes to mdr. In fact, the observed results revealed that this p gp substrate is able to significantly induce p gp expression in a concentration dependent manner, up to 183% for the highest. Pglycoprotein mediated efflux limits substrate and drug. Mk467 may be the substrate to active cellular transport but it does not appear to be a substrate of p gp. Prediction of pglycoprotein substrates by a support. P glycoprotein p gp is involved in the transport of xenobiotic compounds and responsible for the decrease of the drug accumulation in multidrugresistant cells. Pglycoprotein substrate models using support vector machines based on a comprehensive data set article in journal of chemical information and modeling 516. Pgp model a database of 256 chemically diverse compounds with pgp transport properties was assembled from the literature.
Pglycoproteinmediated drug interactions in pregnancy and. P glycoprotein p gp is a drug transporter that effluxes chemotherapeutic drugs and is implicated in the development of resistance of cancer cells to chemotherapeutic drugs. They used autodock vina docking software for the simulations and constructed a web server for docking calculations into the structure of mouse pgp and the homology model of human pgp, which is free for 10 runs by user. Classification of pglycoproteininteracting compounds using. Intracellular accumulation of guanfacine was compared between pgp expressing llcpk1mdr1 cells and pgpnegative llcpk1 cells to evaluate the potential interaction between pgp and guanfacine. Predicting pglycoproteinmediated drug transport based on. From the homology models generated, the one with highest cscore was selected for further refinement. Recognizes if a compound is likely to be a substrate of the pglycoprotein pgp drug efflux pump. Gpinfo combines a comprehensive database of petroleum exploration information with an attractive and easy to use graphical interface for viewing and manipulating data.
Pglycoprotein substrates, inducers, and inhibitors. When issued in the context of a company database, this will tell you the name of the system database that manages it. Human p glycoprotein pgp is a 170 kda polypeptide juliano and ling, 1976 comprising 1280 amino acids chen et al. Openpgp is the most widely used email encryption standard. Pglycoprotein pgp is involved in the transport of xenobiotic compounds and responsible for the decrease of the drug accumulation in multidrugresistant cells. Inhibition of pglycoprotein gene expression and function. If the correlation coefficient between the pgp modulator category substrate or inhibitor and a certain descriptor was. We performed molecular dynamics md simulations to generate fifty sidechain variants for pgp pdb id. Pgp is an atpbinding cassette abc transporter belonging to the abcb subfamily hennessy and spiers, 2007 that functions as a dynamic efflux pump aller et al. The substrate properties of quetiapine to p gp have been studied in ex vivo and in vitro where conflicting results were reported 15,37 38 39. A machine learningbased prediction platform for pglycoprotein.
P glycoprotein mediated efflux limits substrate and drug uptake in a preclinical brain metastases of breast cancer model chris e. Human pglycoprotein pgp is a 170 kda polypeptide juliano and ling, 1976 comprising 1280 amino acids chen et al. Several structural studies of p gp and its homologs have provided insights into its transport cycle, but questions remain regarding how p gp recognizes diverse substrates and how substrate binding is coupled to atp hydrolysis. A computational study of the inhibition mechanisms of p. To get the system database name used to be known as the dynamics database from any gp company, use the following sql. Sep 28, 2010 the best route here in my humble opinion is to run through gp utilities to create the company, and then just restore a backup of the company database over the new empty company created. In this investigation we compare several docking algorithms in order to find the conditions that are able to discriminate between pgp binders and nonbinders. The p gp sequence was taken from uniprot database accession code p08183, and the conformation of the human p gp protein was built using itasser 39, 40 which aligns the query sequence with several templates known structures from the protein data bank library. Understanding the structural basis of pgp, substrate polyspecificity has been hampered by its intrinsic flexibility, which is facilitated by a 75residue linker.
Mk467 may be suitable for use in dogs homozygous negative for the pgp mutation. Our data show that colchicine, a known p gp substrate,,, increased p gp expression in caco2 cells without a concomitant increase in the activity of the protein. There is no single experimental method to conclusively identify a compound as a substrate for p gp. Available natural compound databases serve as an invaluable source to identify novel lead compounds that. In this study, we have built several computational models to predict whether or not a compound is a pgp substrate, based on the largest data set yet published, employing 332 distinct structures. Pglycoprotein substrate models using support vector machines. Compounds 16, 16a, r19 and s19, which all inhibited substrate transport by 20% at concentrations of 20. One p gp substrate is the widely used chemotherapy drug paclitaxel. Categorized as a adenosine triphosphatebinding casette abc drug uptakeefflux transporter. Openpgp was originally derived from the pgp software, created by phil zimmermann. Best pgp substrate models were further validated with three sets of. P gp model a database of 256 chemically diverse compounds with p gp transport properties was assembled from the literature. The need for human breast cancer resistance protein.
Fingerprintbased in silico models for the prediction of p. Therefore, we suggest that patients whose tumors express high levels of pgp be excluded from future clinical trials for vintafolideaswellasotherfrtargetedtherapeuticsbearingapgp substrate. Pglycoprotein pgp functions as a drug efflux pump, mediating multidrug resistance and limiting the efficacy of many drugs. Before the structure of pgp was xray resolved, multiple partly mutually contradictory experimental observations on the points of interaction of substrates and pgp molecule were made. The substrate properties of quetiapine to pgp have been studied in ex vivo and in vitro where conflicting results were reported 15,37 38 39. There are two models, an artificial neural network. In this investigation we compare several docking algorithms in order to find the conditions that are able to discriminate between p gp binders and nonbinders. We performed an in vitro study to determine if guanfacine is indeed a substrate of pgp. Frontiers pglycoprotein mediated efflux limits substrate. Briefly, 5 x 104 lucena 1 or k562 cells ml1 were incubated in duplicate for 1 h, as previously established,4 at 37c with 5% co 2 in 96well plates containing complete rpmi. Pgp induction may influence the central nervous system cns influx availability and potential efficacy of opioid agonists, 21 as many opioids eg, morphine, oxycodone have a high pgp substrate activity, 28 and chronic administration may result in lower brain concentrations. Clearly, identification of potential p gp substrate liability early in the drug discovery process would be advantageous. P glycoprotein p gp is a transporter of great clinical and pharmacological significance.
Pglycoprotein substrate models using support vector. Therefore, in silico methods for predicting pgp substrates and. Multiclass classifier for pglycoprotein substrates, inhibitors. Clearly, identification of potential pgp substrate liability early in the drug discovery process would be advantageous. For instance, an 80fold higher concentration of the known p gp substrate vincristine is required for nciadrres growth inhibition, than for ovcar8 cells figure 2b. Pglycoprotein modulators and its validation by molecular docking. Rapid identification of pglycoprotein substrates and inhibitors. On the mechanism of substratenonsubstrate recognition by. We describe a multiplepharmacophore model that can discriminate between substrates and nonsubstrates of pgp with an accuracy of 63%. The role of pglycoprotein and breast cancer resistance.
Transports drugs out of cells and into intestinal lumen, urine or bile. A computational ensemble pharmacophore model for identifying. We have focused our efforts on developing technologies and products to test properties of. Gpinfo australia petroleum exploration information. Model development models are quantitativestructure property relationships qspr that calculate the toxicity properties of interest in terms of a compounds structural descriptors. The p gp transport of each compound was assigned yes if transported by the protein and no if not transported. Colchicine effect on pglycoprotein expression and activity. Davlbh via the fr, as in vintafolide, fails to overcome pgp mediated ef. M gf120918 although this pgp inhibitor is also known to inhibit bcrp. For instance, an 80fold higher concentration of the known pgp substrate vincristine is required for nciadrres growth inhibition, than for ovcar8 cells figure 2b. However, to build such models, pharmacological data must be collected for both targets, which is a tedious task, often involving manual and poorly reproducible steps. In silico tools to predict inhibition and substrate profiles towards bcrp and p gp might serve as early filters in the drug discovery and development process. Here we present a computational approach that combines docking. Start studying p glycoprotein substrates, inducers, and inhibitors.
Assessment of pglycoprotein pgp, abcb1 affinity in humans is. Pglycoprotein pgp, multidrug resistance protein, mdr1 plays a gatekeeper role, interfering delivery of multiple pharmaceuticals to the target tissues and cells. Microsoft suggest new definition this definition appears very frequently and is found in the following acronym finder categories. Hence, it is crucial to know if a drug is a p gp substrate or inhibitor in view of pharmacokinetics. Biolog is a world leader in cellbased phenotypic testing technologies and assays. The pgp transport of each compound was assigned yes if transported by the protein and no if not transported. The pgp sequence was taken from uniprot database accession code p08183, and the conformation of the human pgp protein was built using itasser 39, 40 which aligns the query sequence with several templates known structures from the protein data bank library. The mechanism of substratenon substrate recognition by pgp is still undiscovered.
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