Comparative in silico prediction of P‐glycoprotein‐mediated transport for 2010–2020 US FDA‐approved drugs using six Web‐tools

Guéniche, Nelly; Huguet, Antoine; Bruyère, Arnaud; Habauzit, Denis; Hégarat, Ludovic Le; Fardel, Olivier

doi:10.1002/bdd.2299

Cited by 9 publications

(10 citation statements)

References 35 publications

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“…All the tested compounds decreased the pBAD at Ser-99 without change in total BAD expression (Figure 6). Since the active compounds (4e, 4f, 4i, and NPB as a comparison) displayed efficacy against MCF-7 cells, the in silico ADMET properties (8 parameters) of these compounds were determined by using vNN-ADMET online platform [29]. The results are tabulated in Table 4.…”

Section: Resultsmentioning

confidence: 99%

Investigation of NPB Analogs That Target Phosphorylation of BAD-Ser99 in Human Mammary Carcinoma Cells

Girimanchanaika

Dukanya

Swamynayaka

et al. 2021

IJMS

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The design and development of a small molecule named NPB [3-{(4(2,3-dichlorophenyl)piperazin-1-yl}{2-hydroxyphenyl)methyl}-N-cyclopentylbenzamide], which specifically inhibited the phosphorylation of BAD at Ser99 in human carcinoma cells has been previously reported. Herein, the synthesis, characterization, and effect on cancer cell viability of NPB analogs, and the single-crystal X-ray crystallographic studies of an example compound (4r), which was grown via slow-solvent evaporation technique is reported. Screening for loss of viability in mammary carcinoma cells revealed that compounds such as 2[(4(2,3-dichlorophenyl)piperazin-1-yl][naphthalen-1-yl]methyl)phenol (4e), 5[(4(2,3-dichlorophenyl)piperazin-1-yl][2-hydroxyphenyl)methyl)uran-2-carbaldehyde (4f), 3[(2-hydroxyphenyl][4(p-tolyl)piperazin-1-yl)methyl)benzaldehyde (4i), and NPB inhibited the viability of MCF-7 cells with IC50 values of 5.90, 3.11, 7.68, and 6.5 µM, respectively. The loss of cell viability was enhanced by the NPB analogs synthesized by adding newer rings such as naphthalene and furan-2-carbaldehyde in place of N-cyclopentyl-benzamide of NPB. Furthermore, these compounds decreased Ser99 phosphorylation of hBAD. Additional in silico density functional theory calculations suggested possibilities for other analogs of NPB that may be more suitable for further development.

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Section: Resultsmentioning

confidence: 99%

Investigation of NPB Analogs That Target Phosphorylation of BAD-Ser99 in Human Mammary Carcinoma Cells

Girimanchanaika

Dukanya

Swamynayaka

et al. 2021

IJMS

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“…For each individual or combination of web tool(s), the area under the receiver operating characteristics curve (ROC AUC) was determined to be the first prediction performance parameter using GraphPad Prism software (version 5.0; GraphPad Software Inc.) as previously described. [ 26 ] The Matthews correlation coefficient (MCC) was then calculated as a second prediction performance parameter. The MCC measures the correlation between predictions and real values.…”

Section: Methodsmentioning

confidence: 99%

“…The MCC measures the correlation between predictions and real values. [ 26 ] Thereafter, the prediction of P‐gp activity inhibition by 762 pesticides belonging to various chemical classes was evaluated using the most efficient individual web tool or combination of tools.…”

Section: Methodsmentioning

confidence: 99%

Combined in silico and in vitro approaches to identify P‐glycoprotein‐inhibiting pesticides

Guéniche,

Lakehal,

Habauzit

et al. 2023

J Biochem & Molecular Tox

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The P‐glycoprotein (P‐gp) efflux pump plays a major role in xenobiotic detoxification. The inhibition of its activity by environmental contaminants remains however rather little characterised. The present study was designed to develop a combination of different approaches to identify P‐gp inhibitors among a large number of pesticides using in silico and in vitro models. First, the prediction performance of four web tools was evaluated alone or in combination using a set of recently marketed drugs. The best combination of web tools—AdmetSAR2.0/PgpRules/pkCSM—was next used to predict P‐gp activity inhibition by 762 pesticides. Among the 187 pesticides predicted to be P‐gp inhibitors, 11 were tested in vitro for their ability to inhibit the efflux of reference substrates (rhodamine 123 and Hoechst 33342) in P‐gp overexpressing MCF7R cells and to inhibit the efflux of the reference substrate rhodamine 123 in the Caco‐2 cell monolayer. In MCF7R cell assays, ivermectin B1a, emamectin B1 benzoate, spinosad, dimethomorph and tralkoxydim inhibited P‐gp activity; ivermectin B1a, emamectin B1 benzoate and spinosad were determined to be stronger inhibitors (half‐maximal inhibitory concentration [IC50] of 3 ± 1, 5 ± 1 and 7 ± 1 µM, respectively) than dimethomorph and tralkoxydim (IC50 of 102 ± 7 and 88 ± 7 µM, respectively). Ivermectin B1a, emamectin B1 benzoate, spinosad and dimethomorph also inhibited P‐gp activity in Caco‐2 cell monolayer assays, with dimethomorph being a weaker P‐gp inhibitor. These combined approaches could be used to identify P‐gp inhibitors among food contaminants, but need to be optimised and adapted for high‐throughput screening.

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“…The in silico models rely on the sequence similarities rather than functional similarities in predicting 3D conformation, which impede their interests as alternatives to the in vitro assays 123 . For instance, a recent study demonstrated that all six freely accessible Web-tools (ADMETlab, AdmetSAR2.0, PgpRules, pkCSM, SwissADME and vNN-ADMET) are poorly to meet the criteria for predicting P-gp-mediated transport 124 .…”

Section: Current Approach In Transporter Studymentioning

confidence: 99%

“…For instance, a recent study demonstrated that all six freely accessible Web-tools (ADMETlab, AdmetSAR2.0, PgpRules, pkCSM, SwissADME and vNN-ADMET) are poorly to meet the criteria for predicting P-gp-mediated transport [124].…”

Section: In Silico Modelsmentioning

confidence: 99%

Transporter-mediated Natural Product-Drug Interactions

Wang

Ding

et al. 2022

Planta Med

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The increasing use of natural products in the clinical practice has raised great concerns about the potential natural product-drug interactions (NDIs). Drug transporters mediate the transmembrane passage of a broad range of drugs and thus are important determinants for drug pharmacokinetics and pharmacodynamics. Generally, transporters can be divided into ATP binding cassette (ABC) family and solute carrier (SLC) family. Numerous natural products have been identified as inhibitors, substrates, inducers, and/or activators of drug transporters. This review article aims to provide a comprehensive summary of the recent progress on the research of NDIs, focusing on the main drug transporters, such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter 1 and 3 (OAT1/OAT3), organic anion-transporting polypeptide 1B1 and 1B3 (OATP1B1/OATP1B3), organic cation transporter 2 (OCT2), multidrug and toxin extrusion protein 1 and 2-K (MATE1/MATE2-K). Additionally, the challenges and strategies of studying NDIs are also discussed.

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Comparative in silico prediction of P‐glycoprotein‐mediated transport for 2010–2020 US FDA‐approved drugs using six Web‐tools

Cited by 9 publications

References 35 publications

Investigation of NPB Analogs That Target Phosphorylation of BAD-Ser99 in Human Mammary Carcinoma Cells

Investigation of NPB Analogs That Target Phosphorylation of BAD-Ser99 in Human Mammary Carcinoma Cells

Combined in silico and in vitro approaches to identify P‐glycoprotein‐inhibiting pesticides

Transporter-mediated Natural Product-Drug Interactions

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