ArticleJournal of computer-aided molecular design2013
In silico model for P-glycoprotein substrate prediction: insights from molecular dynamics and in vitro studies.
Article in Journal of computer-aided molecular design, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 39 citations in OpenAlex.
- Review
- The pH-dependence of efflux ratios determined with bidirectional transport assays across cellular monolayers.International journal of pharmaceutics: X · 2024Article
- Regulation of P-Glycoprotein during Oxidative Stress.Antioxidants (Basel, Switzerland) · 2024Review
- The Alternating Access Mechanism in Mammalian Multidrug Resistance Transporters and Their Bacterial Homologs.Membranes · 2023Article
- 5-Arylidenerhodanines as P-gp Modulators: An Interesting Effect of the Carboxyl Group on ABCB1 Function in Multidrug-Resistant Cancer Cells.International journal of molecular sciences · 2022Article
- Search for ABCB1 Modulators Among 2-Amine-5-Arylideneimidazolones as a New Perspective to Overcome Cancer Multidrug Resistance.Molecules (Basel, Switzerland) · 2020Article
- The reliability of molecular dynamics simulations of the multidrug transporter P-glycoprotein in a membrane environment.PloS one · 2018Article
- Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer.Scientific reports · 2017Article
- Toward Understanding the Catalytic Mechanism of Human Paraoxonase 1: Site-Specific Mutagenesis at Position 192.PloS one · 2016Article
- Pregnane X Receptor and P-glycoprotein: a connexion for Alzheimer's disease management.Molecular diversity · 2014Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
P-glycoprotein (P-gp) is a plasma membrane efflux transporter belonging to ATP-binding cassette superfamily, responsible for multidrug resistance in tumor cells. Over-expression of P-gp in cancer cells limits the efficacy of many anticancer drugs. A clear understanding of P-gp substrate binding will be advantageous in early drug discovery process. However, substrate poly-specificity of P-gp is a limiting factor in rational drug design. In this investigation, we report a dynamic trans-membrane model of P-gp that accurately identified the substrate binding residues of known anticancer agents. The study included homology modeling of human P-gp based on the crystal structure of C. elegans P-gp, molecular docking, molecular dynamics analyses and binding free energy calculations. The model was further utilized to speculate substrate propensity of in-house anticancer compounds. The model demonstrated promising results with one anticancer compound (NSC745689). As per our observations, the molecule could be a potential lead for anticancer agents devoid of P-gp mediated multiple drug resistance. The in silico results were further validated experimentally using Caco-2 cell lines studies, where NSC745689 exhibited poor permeability (P app 1.03 ± 0.16 × 10(-6) cm/s) and low efflux ratio of 0.26.
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