ArticlePLoS computational biology2011
Exhaustive sampling of docking poses reveals binding hypotheses for propafenone type inhibitors of P-glycoprotein.
Article in PLoS computational biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 78 citations in OpenAlex.
- Mechanistic insights into P-glycoprotein ligand transport and inhibition revealed by enhanced molecular dynamics simulations.Computational and structural biotechnology journal · 2024Article
- ATP-Binding Cassette and Solute Carrier Transporters: Understanding Their Mechanisms and Drug Modulation Through Structural and Modeling Approaches.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Ligand- and Structure-based Approaches for Transmembrane Transporter Modeling.Current drug research reviews · 2024Review
- Synergistic Inhibitory Effect of Quercetin and Cyanidin-3O-Sophoroside on ABCB1.International journal of molecular sciences · 2023Article
- Homology Modeling of the Human P-glycoprotein (ABCB1) and Insights into Ligand Binding through Molecular Docking Studies.International journal of molecular sciences · 2020Article
- Rigorous sampling of docking poses unveils binding hypothesis for the halogenated ligands of L-type Amino acid Transporter 1 (LAT1).Scientific reports · 2019Article
- Multiclass Classifier for P-Glycoprotein Substrates, Inhibitors, and Non-Active Compounds.Molecules (Basel, Switzerland) · 2019Article
- Discovery of Potent Inhibitors for the Large Neutral Amino Acid Transporter 1 (LAT1) by Structure-Based Methods.International journal of molecular sciences · 2018Article
- Interspecies comparison of putative ligand binding sites of human, rat and mouse P-glycoprotein.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2018Article
- Structure based classification for bile salt export pump (BSEP) inhibitors using comparative structural modeling of human BSEP.Journal of computer-aided molecular design · 2017Article
- Empowering pharmacoinformatics by linked life science data.Journal of computer-aided molecular design · 2017Article
- From linked open data to molecular interaction: studying selectivity trends for ligands of the human serotonin and dopamine transporter.MedChemComm · 2016Article
- Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer.Molecular bioSystems · 2016Article
- Article
- Prediction of drug-ABC-transporter interaction--Recent advances and future challenges.Advanced drug delivery reviews · 2015Review
- A binding mode hypothesis of tiagabine confirms liothyronine effect on γ-aminobutyric acid transporter 1 (GAT1).Journal of medicinal chemistry · 2015Article
- The ability of molecular docking to unravel the controversy and challenges related to P-glycoprotein--a well-known, yet poorly understood drug transporter.Investigational new drugs · 2014Review
- Modelling three-dimensional protein structures for applications in drug design.Drug discovery today · 2014Review
- Reversible dimers of the atypical antipsychotic quetiapine inhibit p-glycoprotein-mediated efflux in vitro with increased binding affinity and in situ at the blood-brain barrier.ACS chemical neuroscience · 2014Article
- Ligand and structure-based classification models for prediction of P-glycoprotein inhibitors.Journal of chemical information and modeling · 2014Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Overexpression of the xenotoxin transporter P-glycoprotein (P-gp) represents one major reason for the development of multidrug resistance (MDR), leading to the failure of antibiotic and cancer therapies. Inhibitors of P-gp have thus been advocated as promising candidates for overcoming the problem of MDR. However, due to lack of a high-resolution structure the concrete mode of interaction of both substrates and inhibitors is still not known. Therefore, structure-based design studies have to rely on protein homology models. In order to identify binding hypotheses for propafenone-type P-gp inhibitors, five different propafenone derivatives with known structure-activity relationship (SAR) pattern were docked into homology models of the apo and the nucleotide-bound conformation of the transporter. To circumvent the uncertainty of scoring functions, we exhaustively sampled the pose space and analyzed the poses by combining information retrieved from SAR studies with common scaffold clustering. The results suggest propafenone binding at the transmembrane helices 5, 6, 7 and 8 in both models, with the amino acid residue Y307 playing a crucial role. The identified binding site in the non-energized state is overlapping with, but not identical to, known binding areas of cyclic P-gp inhibitors and verapamil. These findings support the idea of several small binding sites forming one large binding cavity. Furthermore, the binding hypotheses for both catalytic states were analyzed and showed only small differences in their protein-ligand interaction fingerprints, which indicates only small movements of the ligand during the catalytic cycle.
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