In Silico Prediction of the Site of Oxidation by Cytochrome P450 3A4 That Leads to the Formation of the Toxic Metabolites of Pyrrolizidine Alkaloids

2015 ◽  
Vol 28 (4) ◽  
pp. 702-710 ◽  
Author(s):  
Muluneh M. Fashe ◽  
Risto O. Juvonen ◽  
Aleksanteri Petsalo ◽  
Jouko Vepsäläinen ◽  
Markku Pasanen ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
In Silico ◽  
Pyrrolizidine Alkaloids ◽  
Cytochrome P450 3A4 ◽  
In Silico Prediction ◽  
Toxic Metabolites

scholarly journals Multidrug Resistance Reversal Effects of Aminated Thioxanthones and Interaction with Cytochrome P450 3A4

2011 ◽  
Vol 15 (1) ◽  
pp. 31 ◽  
Author(s):  
Andreia Palmeira ◽  
Maria Emília Sousa ◽  
Miguel X Fernandes ◽  
Madalena M. Pinto ◽  
M. Helena Vasconcelos
Keyword(s):  
Cytochrome P450 ◽  
Multidrug Resistance ◽  
In Silico ◽  
Mammalian Cells ◽  
Leukemia Cell ◽  
Membrane Vesicles ◽  
Cytochrome P450 3A4 ◽  
Cancer Resistance ◽  
In Silico Prediction

Purpose. Aminated thioxanthones have recently been described as dual-acting agents: growth inhibitors of leukemia cell lines and P-glycoprotein (P-gp) inhibitors. To evaluate the selectivity profile of thioxanthones as inhibitors of multidrug resistance (MDR), their interaction with other ABC transporters, which were found to have a strong correlation with multidrug resistance, such as multidrug resistant proteins 1 (MRP1), 2 (MRP2) and 3 (MRP3) and breast cancer resistance protein (BCRP) was also evaluated. The interaction of thioxanthones with cytochrome P450 3A4 (CYP3A4) together with the prediction of their binding conformations and metabolism sites was also investigated. Methods. The UIC2 monoclonal antibody-labelling assay was performed using P-gp overexpressing leukemia cells, K562Dox, incubated with eight thioxanthonic derivatives, in order to confirm their P-gp inhibitory activity. A colorimetric-based ATPase assay using membrane vesicles from mammalian cells overexpressing a selected human ABC transporter protein (P-gp, MRP1, MRP2, MRP3, or BCRP) was performed. To verify if some of the thioxanthonic derivatives were substrates or inhibitors of CYP3A4, a luciferin-based luminescence assay was performed. Finally, the in silico prediction of the most probable metabolism sites and docking studies of thioxanthones on CYP3A4 binding site were investigated. Results. Thioxanthones interacted not only with P-gp but also with MRP and BCRP transporters. These compounds also interfere with CYP3A4 activity in vitro, in accordance with the in silico prediction. Conclusion. Thioxanthonic derivatives are multi-target compounds. A better characterization of the interactions of these compounds with classical resistance mechanisms may possibly identify improved treatment applications. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Screening of cytochrome P450 3A4 inhibitors via in silico and in vitro approaches

RSC Advances ◽  
2018 ◽  
Vol 8 (61) ◽  
pp. 34783-34792 ◽  
Author(s):  
Xiaocong Pang ◽  
Baoyue Zhang ◽  
Guangyan Mu ◽  
Jie Xia ◽  
Qian Xiang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Virtual Screening ◽  
In Silico ◽  
Cytochrome P450 3A4 ◽  
Important Member ◽  
Cyp3a4 Inhibitors

Cytochrome P450 3A4 (CYP3A4) is an important member of the CYP family and responsible for metabolizing a broad range of drugs. It is necessary to establish virtual screening models for predicting CYP3A4 inhibitors.

scholarly journals In Silico Prediction of Cytochrome P450-Drug Interaction: QSARs for CYP3A4 and CYP2C9

2016 ◽  
Vol 17 (6) ◽  
pp. 914 ◽  
Author(s):  
Serena Nembri ◽  
Francesca Grisoni ◽  
Viviana Consonni ◽  
Roberto Todeschini
Keyword(s):  
Cytochrome P450 ◽  
Drug Interaction ◽  
In Silico ◽  
In Silico Prediction

In Silico Prediction of Cytochrome P450-Mediated Site of Metabolism (SOM)

2013 ◽  
Vol 20 (3) ◽  
pp. 279-289
Author(s):  
Xian Liu ◽  
Qiancheng Shen ◽  
Jing Li ◽  
Shanshan Li ◽  
Cheng Luo ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
In Silico ◽  
In Silico Prediction

Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation

2008 ◽  
Vol 43 (6) ◽  
pp. 1171-1179 ◽  
Author(s):  
Mattijs K. Julsing ◽  
Nikolay P. Vasilev ◽  
Dina Schneidman-Duhovny ◽  
Remco Muntendam ◽  
Herman J. Woerdenbag ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
In Silico ◽  
Experimental Validation ◽  
Cytochrome P450 3A4 ◽  
In Silico Predictions

Integrated in Silico−in Vitro Strategy for Addressing Cytochrome P450 3A4 Time-Dependent Inhibition

2010 ◽  
Vol 23 (3) ◽  
pp. 664-676 ◽  
Author(s):  
Michael Zientek ◽  
Chad Stoner ◽  
Robyn Ayscue ◽  
Jacquelyn Klug-McLeod ◽  
Ying Jiang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
In Silico ◽  
Time Dependent ◽  
Cytochrome P450 3A4 ◽  
Dependent Inhibition ◽  
Time Dependent Inhibition
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