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.

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

scholarly journals Inhibitory Effects of Salinispora-derived Metabolites Against Multidrug Resistance: An In-silico Study

2021 ◽  
Author(s):  
Morteza Ghandadi
Keyword(s):  
Multidrug Resistance ◽  
Abc Transporters ◽  
In Silico ◽  
Docking Studies ◽  
Bioactive Metabolites ◽  
Multi Drug Resistance ◽  
Cancer Resistance ◽  
Resistance Protein

Background: Multi Drug Resistance (MDR) is known to defeat most chemotherapies as one of the main anticancer strategies. The role of overexpression or overactivation of ATPBinding Cassette (ABC) transporters, especially P-glycoprotein (P-gp), in the development of chemotherapy has long been demonstrated. Salinispora is a marine actinomycete genus known for the production of novel bioactive metabolites. Objectives: In this study, the potential of Salinispora derived metabolites as inhibitor of ATPbinding cassette (ABC) transports have been investigated using in-silico approaches. Methods: Physicochemical, pharmacokinetic and drug likeness of the Salinispora derived metabolites have been analyzed using SwissADME server. This was accompanied by the employment of docking strategy to evaluate anti-MDR potential of the metabolites using P-gp, Breast Cancer Resistance Protein (BCRP) and Multidrug Resistance Protein 1 (MRP-1) as target proteins. Results: Nineteen metabolites were found to have demonstrated appropriate physicochemical, pharmacokinetic, and drug-likeness properties and were involved in the docking studies. Based on docking studies, saliniquinones, cyclomarazine, and cyanosporoside A demonstrated ABC transporters inhibitory potential. Conclusion: Our results suggest that further in vivo and in vitro studies on anti-MDR effects of Salinispora-derived metabolites are warranted.

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 In Silico Predicted Antifungal Peptides: In Vitro and In Vivo Anti-Candida Activity

2021 ◽  
Vol 7 (6) ◽  
pp. 439
Author(s):  
Tecla Ciociola ◽  
Walter Magliani ◽  
Tiziano De Simone ◽  
Thelma A. Pertinhez ◽  
Stefania Conti ◽  
...  
Keyword(s):  
In Silico ◽  
Mammalian Cells ◽  
Galleria Mellonella ◽  
Ex Vivo ◽  
Consensus Sequence ◽  
In Silico Analysis ◽  
Significant Activity ◽  
Synthetic Antibody

It has been previously demonstrated that synthetic antibody-derived peptides could exert a significant activity in vitro, ex vivo, and/or in vivo against microorganisms and viruses, as well as immunomodulatory effects through the activation of immune cells. Based on the sequence of previously described antibody-derived peptides with recognized antifungal activity, an in silico analysis was conducted to identify novel antifungal candidates. The present study analyzed the candidacidal and structural properties of in silico designed peptides (ISDPs) derived by amino acid substitutions of the parent peptide KKVTMTCSAS. ISDPs proved to be more active in vitro than the parent peptide and all proved to be therapeutic in Galleria mellonella candidal infection, without showing toxic effects on mammalian cells. ISDPs were studied by circular dichroism spectroscopy, demonstrating different structural organization. These results allowed to validate a consensus sequence for the parent peptide KKVTMTCSAS that may be useful in the development of novel antimicrobial molecules.

scholarly journals In Silico Structural Modeling and Analysis of Interactions of Tremellomycetes Cytochrome P450 Monooxygenases CYP51s with Substrates and Azoles

2021 ◽  
Vol 22 (15) ◽  
pp. 7811
Author(s):  
Olufunmilayo Olukemi Akapo ◽  
Joanna M. Macnar ◽  
Justyna D. Kryś ◽  
Puleng Rosinah Syed ◽  
Khajamohiddin Syed ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Structural Analysis ◽  
In Silico ◽  
Web Application ◽  
Cytochrome P450 Monooxygenases ◽  
Agglomerative Clustering ◽  
Ligand Complex ◽  
P450 Monooxygenase ◽  
Study Results

Cytochrome P450 monooxygenase CYP51 (sterol 14α-demethylase) is a well-known target of the azole drug fluconazole for treating cryptococcosis, a life-threatening fungal infection in immune-compromised patients in poor countries. Studies indicate that mutations in CYP51 confer fluconazole resistance on cryptococcal species. Despite the importance of CYP51 in these species, few studies on the structural analysis of CYP51 and its interactions with different azole drugs have been reported. We therefore performed in silico structural analysis of 11 CYP51s from cryptococcal species and other Tremellomycetes. Interactions of 11 CYP51s with nine ligands (three substrates and six azoles) performed by Rosetta docking using 10,000 combinations for each of the CYP51-ligand complex (11 CYP51s × 9 ligands = 99 complexes) and hierarchical agglomerative clustering were used for selecting the complexes. A web application for visualization of CYP51s’ interactions with ligands was developed (http://bioshell.pl/azoledocking/). The study results indicated that Tremellomycetes CYP51s have a high preference for itraconazole, corroborating the in vitro effectiveness of itraconazole compared to fluconazole. Amino acids interacting with different ligands were found to be conserved across CYP51s, indicating that the procedure employed in this study is accurate and can be automated for studying P450-ligand interactions to cater for the growing number of P450s.

In silico prediction, LC-HRMS/MS analysis, and targeted/untargeted data-mining workflow for the profiling of phenylfentanyl in vitro metabolites

Talanta ◽  
2021 ◽  
pp. 122740
Author(s):  
Annagiulia Di Trana ◽  
Pietro Brunetti ◽  
Raffaele Giorgetti ◽  
Enrico Marinelli ◽  
Simona Zaami ◽  
...  
Keyword(s):  
Data Mining ◽  
In Silico ◽  
In Silico Prediction ◽  
Ms Analysis

scholarly journals Kaempferol-Mediated Sensitization Enhances Chemotherapeutic Efficacy of Sorafenib Against Hepatocellular Carcinoma: An In Silico and In Vitro Approach

2020 ◽  
Vol 10 (3) ◽  
pp. 472-476
Author(s):  
Bhagyalakshmi Nair ◽  
Ruby John Anto ◽  
Sabitha M ◽  
Lekshmi R. Nath
Keyword(s):  
Hepatocellular Carcinoma ◽  
Multidrug Resistance ◽  
Liver Cancer ◽  
In Silico ◽  
Culture Media ◽  
Positive Control ◽  
Advanced Hepatocellular Carcinoma ◽  
Discovery Studio ◽  
Toxic Concentrations

Purpose : Sorafenib is the sole FDA approved drug conventionally used for the treatment of advanced hepatocellular carcinoma (HCC). Despite of the beneficial use of sorafenib in the treatment of HCC, multidrug resistance still remains a challenge. HCC is inherently known as chemotherapy resistant tumor due to P-glycoprotein (P-gp)-mediated multidrug resistance. Methods: We studied the interaction energy of kaempferol with human multidrug resistance protein-1 (RCSB PDB ID: 2CBZ) using in silico method with the help of BIOVIA Discovery Studio. HepG2 and N1S1 liver cancer cell lines were treated in suitable cell culture media to evaluate the efficacy of kaempferol in chemo-sensitizing liver cancer cells towards the effect of sorafenib. Cell viability study was performed by MTT assay. Results: In silico analysis of kaempferol showed best docking score of 23.14 with Human Multi Drug Resistant Protein-1 (RCSB PDB ID: 2CBZ) compared with positive control verapamil. In in-vitro condition, combination of sub-toxic concentrations of both kaempferol and sorafenib produced 50% cytotoxicity with concentration of 2.5 µM each which indicates that kaempferol has the ability to reverse the MDR by decreasing the over-expression of P-gp. Conclusion: Kaempferol is able to sensitize the HepG2 and N1S1 against the sub-toxic concentration of sorafenib. Hence, we consider that the efficacy of sorafenib chemotherapy can be enhanced by the significant approach of combining the sub-toxic concentrations of sorafenib with kaempferol. Thus, kaempferol can be used as a better candidate molecule along with sorafenib for enhancing its efficacy, if validated through preclinical studies.

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