P-Glycoprotein Efflux Transporters and Its Resistance Its Inhibitors and Therapeutic Aspects

Karthika, Chenmala; Sureshkumar, Raman

doi:10.5772/intechopen.90430

Cited by 13 publications

(14 citation statements)

References 92 publications

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“…Another important parameter considered was the ability of a drug to be eliminated from the central nervous system (CNS) to reduce toxicity in the cells. P-glycoproteins are ATP-dependent efflux transporters extensively distributed and expressed in cells found in the kidney, liver, colon and pancreas [ 95 ]. They transport toxins and a wide range of foreign substances including drugs, out of the cell.…”

Section: Resultsmentioning

confidence: 99%

“…They transport toxins and a wide range of foreign substances including drugs, out of the cell. Consequently, the overexpression of these proteins in diseased cells reduces the chances of successful drug delivery and limits the cellular uptake of drugs from the blood stream into cells [ 95 , 96 ]. As a result, compounds shortlisted in the study were predicted to be P-gp non-substrates ( Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

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Computational Study on Potential Novel Anti-Ebola Virus Protein VP35 Natural Compounds

et al. 2021

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Ebola virus (EBOV) is one of the most lethal pathogens that can infect humans. The Ebola viral protein VP35 (EBOV VP35) inhibits host IFN-α/β production by interfering with host immune responses to viral invasion and is thus considered as a plausible drug target. The aim of this study was to identify potential novel lead compounds against EBOV VP35 using computational techniques in drug discovery. The 3D structure of the EBOV VP35 with PDB ID: 3FKE was used for molecular docking studies. An integrated library of 7675 African natural product was pre-filtered using ADMET risk, with a threshold of 7 and, as a result, 1470 ligands were obtained for the downstream molecular docking using AutoDock Vina, after an energy minimization of the protein via GROMACS. Five known inhibitors, namely, amodiaquine, chloroquine, gossypetin, taxifolin and EGCG were used as standard control compounds for this study. The area under the curve (AUC) value, evaluating the docking protocol obtained from the receiver operating characteristic (ROC) curve, generated was 0.72, which was considered to be acceptable. The four identified potential lead compounds of NANPDB4048, NANPDB2412, ZINC000095486250 and NANPDB2476 had binding affinities of −8.2, −8.2, −8.1 and −8.0 kcal/mol, respectively, and were predicted to possess desirable antiviral activity including the inhibition of RNA synthesis and membrane permeability, with the probable activity (Pa) being greater than the probable inactivity (Pi) values. The predicted anti-EBOV inhibition efficiency values (IC50), found using a random forest classifier, ranged from 3.35 to 11.99 μM, while the Ki values ranged from 0.97 to 1.37 μM. The compounds NANPDB4048 and NANPDB2412 had the lowest binding energy of −8.2 kcal/mol, implying a higher binding affinity to EBOV VP35 which was greater than those of the known inhibitors. The compounds were predicted to possess a low toxicity risk and to possess reasonably good pharmacological profiles. Molecular dynamics (MD) simulations of the protein–ligand complexes, lasting 50 ns, and molecular mechanisms Poisson-Boltzmann surface area (MM-PBSA) calculations corroborated the binding affinities of the identified compounds and identified novel critical interacting residues. The antiviral potential of the molecules could be confirmed experimentally, while the scaffolds could be optimized for the design of future novel anti-EBOV chemotherapeutics.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Computational Study on Potential Novel Anti-Ebola Virus Protein VP35 Natural Compounds

et al. 2021

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“…P-gp is an active member of the ATP-binding cassette (ABC) protein subfamily, which effluxes a wide range of therapeutic drugs from cells, resulting in multidrug resistance [14]. However, it has an amazing protective effect on normal cells and the outflow of dangerous and foreign compounds [109].…”

Section: Authors' Perspectivementioning

confidence: 99%

“…P-gp is overexpressed in many tumour types, which consider chemotherapeutic drugs foreign bodies and efflux them out of the cancer cells, reducing the therapeutic concentration of drug insider the cancer cells [14]. Cytotoxic medicines that disrupt DNA replication processes, killing rapidly reproducing cancer cells, are particularly vulnerable to P-gp overactivity.…”

Section: Introductionmentioning

confidence: 99%

Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein

Karthika

Sureshkumar

Zehravi

et al. 2022

Life

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P-glycoprotein (P-gp) is a major factor in the multidrug resistance phenotype in cancer cells. P-gp is a protein that regulates the ATP-dependent efflux of a wide range of anticancer medicines and confers resistance. Due to its wide specificity, several attempts have been made to block the action of P-gp to restore the efficacy of anticancer drugs. The major goal has been to create molecules that either compete with anticancer medicines for transport or function as a direct P-gp inhibitor. Despite significant in vitro success, there are presently no drugs available in the clinic that can “block” P-gp–mediated resistance. Toxicity, unfavourable pharmacological interactions, and a variety of pharmacokinetic difficulties might all be the reason for the failure. On the other hand, P-gp has a significant effect in the body. It protects the vital organs from the entry of foreign bodies and other toxic chemicals. Hence, the inhibitors of P-gp should not hinder its action in the normal cells. To develop an effective inhibitor of P-gp, thorough background knowledge is needed in this field. The main aim of this review article was to set forth the merits and demerits of the action of P-gp on cancer cells as well as on normal cells. The influence of P-gp on cancer drug delivery and the contribution of P-gp to activating drug resistance were also mentioned.

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“…There are two main classified roles of p-glycoprotein: substrate and inhibitor. The first one is merge action of compound with this protein system while the other compound may prohibit p-glycoprotein action [30].…”

Section: Figure (6)mentioning

confidence: 99%

In Silico Taste–Toxicity Study of New Hypothetical Hetero-Abiraterone Derivatives

Khalaf¹

2022

IJOIR

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First Iraqi attempt to study drug used for prostate cancer treatment (Abiraterone) that hypothetically reacted with known chemicals classified as Anticancer drug: Tirapazamine (T) and 5-Fluorouracil (F), food additive and preservative: Butylated Hydroxy Toluene (B) and Ethoxyquin (E), and sweeteners: P-4000 (P), Sodium Cyclamate (CS), Alitame (AT), and Saccharin (SA). The second step in this work was computational study of all reactants and the formed products having newly ether, amine, and carboxylic acid ester, and sulphonate bonds by online websites. Taste, toxicity, and ADMET were calculated by three online websites related to Charite University of Medicine, Institute for Physiology, Germany and University of Melbourne, Australia. SMILES of the reactants were obtained from National Library of Medicine/ National Center for Biotechnology Information websites while products were drawn by the molecular editor CS ChemDraw Ultra and rechecked by MarvinSketch program. This in Silico study showed various results of the formed products compared to Abiraterone (A) that predicated it as sour chemical belongs to Class 4 as a harmful substance if swallowed. Abiraterone (A) toxicity on liver organ was 61% probability percentage as hepatotoxicity while carcinogenicity, Immunotoxicity, Mutagenicity, cytotoxicity, AhR, AR, Aromatase, ER, HSE, and p53 were more than 70 % to bind Progesterone or Androgen. Also, Abiraterone (A) has a poor water solubility leading to high intestinal absorption, moderate total clearance, and giving inhibition reaction to Cytochrome P450 type CYP2C19, hERG II, and Ames test. These results confirmed that Abiraterone is structurally less harmful acute class with highly chance to interact with cell components resulting lethal response. All Abiraterone hypothetical products had a harmful reaction if swelled (Class 4), sour taste. All toxicological characters may be highly affected by its water solubility and intestinal absorption towards CNS, BBB, and CaCO2 permeability, skin sensation, and Ames test issues. For example, this in Silico- QSAR foundations about Abiraterone – Saccharin (A-SA) suggest that A-SA is structurally safe and there are several possibilities of becoming an active–multiple toxicological compound.

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P-Glycoprotein Efflux Transporters and Its Resistance Its Inhibitors and Therapeutic Aspects

Cited by 13 publications

References 92 publications

Computational Study on Potential Novel Anti-Ebola Virus Protein VP35 Natural Compounds

Computational Study on Potential Novel Anti-Ebola Virus Protein VP35 Natural Compounds

Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein

In Silico Taste–Toxicity Study of New Hypothetical Hetero-Abiraterone Derivatives

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