A topological substructural approach for the prediction of P-glycoprotein substrates

Cabrera, Miguel A.; González, Isabel Chirivella; Vilas, Carlos; Navarro, Carmen; Bermejo, Marival

doi:10.1002/jps.20449

Cited by 59 publications

(62 citation statements)

References 74 publications

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“…them to diffuse across the lipid bilayer relatively easily (Cabrera et al, 2006;Cianchetta et al, 2005;Crivori et al, 2006;Penzotti et al, 2002;Wang et al, 2003).…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Polarized P-glycoprotein expression by the immortalised human brain endothelial cell line, hCMEC/D3, restricts apical-to-basolateral permeability to rhodamine 123

et al. 2009

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Polarized P-glycoprotein expression by the immortalised human brain endothelial cell line, hCMEC/D3, restricts apical-to-basolateral permeability to rhodamine 123 Leon M. Tai This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. PMSF, phenylmethylsulphonyl fluoride; rh123, rhodamine 123; EM, electron microscopy. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT-1 - A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT

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“…them to diffuse across the lipid bilayer relatively easily (Cabrera et al, 2006;Cianchetta et al, 2005;Crivori et al, 2006;Penzotti et al, 2002;Wang et al, 2003).…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Polarized P-glycoprotein expression by the immortalised human brain endothelial cell line, hCMEC/D3, restricts apical-to-basolateral permeability to rhodamine 123

et al. 2009

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“…In addition, from the point of view of early absorption, distribution, metabolism, and excretion (ADME) prediction of therapeutic agents, various computational prediction models have been reported for ligand interactions with P-gp. 2,[4][5][6][7][8][9][10] In general, a P-gp substrate seems to be lipophilic or amphiphilic, having a large size or molecular volume, electronegative groups and hydrogen bonding groups. 11) Although X-ray structures of the complex of mouse P-gp with enantiomeric cyclic peptide inhibitors have been reported previously by Aller et al in 2009, 12) the mechanism of P-gp substrate/inhibitor recognition is complicated and still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Substrate recognition by P-glycoprotein efflux transporters: Structure-ATPase activity relationship of diverse chemicals and agrochemicals

et al. 2013

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P-glycoprotein (P-gp) is a member of the ATP-binding cassette transporter family. It actively transports a wide variety of compounds out of cells and functions as an energy-dependent efflux pump to protect humans from xenobiotics. P-gp also plays an important role in multidrug resistance in the treatment of cancers. However, the mechanism of P-gp substrate recognition is complicated and still poorly understood. In this study, we screened diverse chemicals, especially agrochemicals by measuring the ATPase activity of human P-gp and found that several classes of chemicals including dibenzoylhydrazine (DBH) insecticides could be substrates of P-gp. ATPase activity was quantitatively analyzed using a 3D quantitative structure-activity relationship, comparative molecular field analysis (CoMFA), and the favorable and unfavorable properties of ligands for ATPase activity were clarified. We also performed a docking simulation of a DBH-type compound with P-gp to predict the binding mode, which was supported by the CoMFA results.

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“…A total of 261 compounds which were classified as P-gp substrates or nonsubstrates used in this work were cautiously assembled from literature. 10,15,16,20 After removing 12 compounds of overlap data, we constructed SD file format of 261 compounds using PreADMET S/W. 21 The data set consists of 146 substrates and 115 nonsubstrates.…”

Section: Methodsmentioning

confidence: 99%

“…9, 10 The prediction of Pgp substrates, which facilitates early identification and elimination of drug candidates of low efficacy or high potential of MDR. [11][12][13][14][15][16][17] However, the accurate prediction of P-gp remains a challenge due to the complexity of the understanding physiological mechanisms and the lack of high quality data.…”

Section: Introductionmentioning

confidence: 99%

Prediction Models of P-Glycoprotein Substrates Using Simple 2D and 3D Descriptors by a Recursive Partitioning Approach

Joung

Kim

et al. 2012

Bulletin of the Korean Chemical Society

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P-gp (P-glycoprotein) is a member of the ATP binding cassette (ABC) family of transporters. It transports many kinds of anticancer drugs out of the cell. It plays a major role as a cause of multidrug resistance (MDR). MDR function may be a cause of the failure of chemotherapy in cancer and influence pharmacokinetic properties of many drugs. Hence classification of candidate drugs as substrates or nonsubstrate of the P-gp is important in drug development. Therefore to identify whether a compound is a P-gp substrate or not, in silico method is promising. Recursive Partitioning (RP) method was explored for prediction of P-gp substrate. A set of 261 compounds, including 146 substrates and 115 nonsubstrates of P-gp, was used to training and validation. Using molecular descriptors that we can interpret their own meaning, we have established two models for prediction of P-gp substrates. In the first model, we chose only 6 descriptors which have simple physical meaning. In the training set, the overall predictability of our model is 78.95%. In case of test set, overall predictability is 69.23%. Second model with 2D and 3D descriptors shows a little better predictability (overall predictability of training set is 79.29%, test set is 79.37%), the second model with 2D and 3D descriptors shows better discriminating power than first model with only 2D descriptors. This approach will be used to reduce the number of compounds required to be run in the P-gp efflux assay.

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A topological substructural approach for the prediction of P-glycoprotein substrates

Cited by 59 publications

References 74 publications

Polarized P-glycoprotein expression by the immortalised human brain endothelial cell line, hCMEC/D3, restricts apical-to-basolateral permeability to rhodamine 123

Polarized P-glycoprotein expression by the immortalised human brain endothelial cell line, hCMEC/D3, restricts apical-to-basolateral permeability to rhodamine 123

Substrate recognition by P-glycoprotein efflux transporters: Structure-ATPase activity relationship of diverse chemicals and agrochemicals

Prediction Models of P-Glycoprotein Substrates Using Simple 2D and 3D Descriptors by a Recursive Partitioning Approach

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