Computational Pharmacogenetics of P-Glycoprotein Mediated Antiepileptic Drug Resistance

Varghese, Sindhu; Palaniappan, Ashok

doi:10.2174/1875036201811010197

Cited by 3 publications

(2 citation statements)

References 45 publications

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“…The following metazoan, algal and bacterial crystal structures were selected as potential templates for homology modeling (38). This justifies their use as templates for MSA in all subsequent steps.…”

Section: Resultsmentioning

confidence: 99%

Computational studies of drug repurposing targeting P-glycoprotein mediated multidrug-resistance phenotypes in agents of neglected tropical diseases

Jaishankar¹,

Muthamilselvan

Palaniappan

2020

Preprint

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Mammalian ABCB1 P-glycoprotein is an ATP- dependent efflux pump with broad substrate specificity associated with cellular drug resistance. Homologous to this role in mammalian biology, the P-glycoprotein of agents of neglected tropical diseases (NTDs) mediates the emergence of multidrug-resistance phenotypes. The clinical and socioeconomic implications of NTDs are exacerbated by the lack of research interest among Big Pharma for treating such conditions. This work aims to characterise P-gp homologues in certain agents of key NTDs, namely Protozoa: Leishmania major, Trypanosoma cruzi;Helminths: Onchocerca volvulus, Schistosoma mansoni.PSI-BLAST searches against the genome of each of these organisms confirmed the presence of P-gp homologues. Each homologue was aligned against five P-gp sequences of known structure, to identify the most suitable template based on sequence homology, phylogenetic nearest neighbor, and query coverage. Antibiotics used in the current line of therapy against each of these pathogens were identified using PubChem and their SMILES structures were converted to PDB using BABEL software. Potential antibiotics to test against the set of FDA-approved antibiotics were identified based on similarity to the chemical class of the known drugs and repurposing of the existing drugs. Docking studies of the respective modelled Pgp structures and the set of antibiotic ligands were carried out using AutoDock and the most tenable target-ligand conformations were assessed. The interacting residues within 4.5 Å of the ligand were identified, and the binding pockets were studied. The relative efficacy of the new drugs and the interacting pump residues were identified. Our studies could lay the foundation for the development of effective synergistic or new therapies against key neglected tropical diseases.

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Section: Resultsmentioning

confidence: 99%

Computational studies of drug repurposing targeting P-glycoprotein mediated multidrug-resistance phenotypes in agents of neglected tropical diseases

Jaishankar¹,

Muthamilselvan

Palaniappan

2020

Preprint

Self Cite

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show abstract

“…Certain metazoan, algal and bacterial crystal structures shown in Table 2 were selected as potential templates for homology modeling [38].…”

Section: Template Selection and Multiple Sequence Alignmentmentioning

confidence: 99%

Computational Studies of Drug Repurposing Targeting P-Glycoprotein-Mediated Multidrug-Resistance Phenotypes in Agents of Neglected Tropical Diseases

Jaishankar¹,

Muthamilselvan

Palaniappan

2020

E. Coli Infections - Importance of Early Diagnosis and Efficient Treatment

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Mammalian ABCB1 P-glycoprotein is an ATP-dependent efflux pump with broad substrate specificity associated with cellular drug resistance. Homologous to this role in mammalian biology, the P-glycoprotein of agents of neglected tropical diseases (NTDs) mediates the emergence of multidrug-resistance phenotypes. The clinical and socioeconomic implications of NTDs are exacerbated by the lack of research interest among Big Pharma for treating such conditions. This work aims to characterise P-gp homologues in certain agents of key NTDs, namely (1) Protozoa: Leishmania major, Trypanosoma cruzi; (2) Helminths: Onchocerca volvulus, Schistosoma mansoni. Based on structural modelling of the organismal P-gp homologues, potential antibiotics targeting these structures were identified based on similarity and repurposing of existing drugs. Docking studies of the Pgp receptor-antibiotic ligand complexes were carried out and the most tenable target-ligand conformations assessed. The interacting residues were identified, and binding pockets studied. The in silico studies yielded measurements of the relative efficacy of the new drugs, which need experimental validation. Our studies could lay the foundation for the development of effective synergistic or new therapies against key neglected tropical diseases. The potential mechanisms of multidrug resistance emergence in E. coli were examined.

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Reversal of P-glycoprotein Mediated Multidrug Resistance in MCF-7/R Cancer Cells by Esculetin Derivatives: Experimental and MD Simulation Studies

Kumbhar,

Khan,

Bavi

et al. 2024

AJBLS

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Coumarins of natural origin have been explored as potential inhibitors of P-glycoprotein (P-gp). Esculetin which belongs to the class of coumarin has been derivatized with known hydrazine pharmacophores viz; benzoyl hydrazine (BH), isonicotinyl hydrazine (INH), and hydrazino benzoic acid. The homology modeling approach was used to predict the three-dimensional structure of human P-gp. An <i>in-silico</i> study has been performed for the structural insight into the molecular mechanism of P-gp inhibition of the esculetin derivatives by molecular docking (MD) and simulation studies. The cell cytotoxic activities of the synthesized compounds were evaluated using in-vitro studies. The sublines resistant doxorubicin (MCF-7/R) were generated and the activities of P-gp proteins were estimated using fluorescent dye accumulation assays. The E-BH showed promising P-gp inhibitory activity and cell cytotoxicity against MCF7 and MCF7/R (resistant) breast cancer cell lines. In line with experimental observations, the E-BH (Esculetin benzoyl hydrazine) has yielded the lowest energy stable complex with P-gp and is stabilized by intermolecular hydrogen bonding and more hydrophobic interactions during 100 ns of simulation. This suggested that the activity of P-gp is probably controlled by hydrophobic interactions. Performed experimental and computational studies has helped to elucidate the mechanism of P-gp inhibition by E-BH. Thus, amongst the three derivatives; E-BH exhibits greater efficacy in blocking the efflux mechanism.

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Computational Pharmacogenetics of P-Glycoprotein Mediated Antiepileptic Drug Resistance

Cited by 3 publications

References 45 publications

Computational studies of drug repurposing targeting P-glycoprotein mediated multidrug-resistance phenotypes in agents of neglected tropical diseases

Computational studies of drug repurposing targeting P-glycoprotein mediated multidrug-resistance phenotypes in agents of neglected tropical diseases

Computational Studies of Drug Repurposing Targeting P-Glycoprotein-Mediated Multidrug-Resistance Phenotypes in Agents of Neglected Tropical Diseases

Reversal of P-glycoprotein Mediated Multidrug Resistance in MCF-7/R Cancer Cells by Esculetin Derivatives: Experimental and MD Simulation Studies

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