ArticleComputational and structural biotechnology journal2019
An Energetically Favorable Ligand Entrance Gate of a Multidrug Transporter Revealed by Partial Nudged Elastic Band Simulations.
Article in Computational and structural biotechnology journal, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed, 7 citations in OpenAlex.
- Coupling the role of lipids to the conformational dynamics of the ABC transporter P-glycoprotein.Biophysical journal · 2024Article
- Membrane-assisted tariquidar access and binding mechanisms of human ATP-binding cassette transporter P-glycoprotein.Frontiers in molecular biosciences · 2024Article
- How does nintedanib overcome cancer drug-resistant mutation of RET protein-tyrosine kinase: insights from molecular dynamics simulations.Journal of molecular modeling · 2021Article
- Computational Insights into Allosteric Conformational Modulation of P-Glycoprotein by Substrate and Inhibitor Binding.Molecules (Basel, Switzerland) · 2020Article
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Authors and funding
5 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
P-glycoprotein (P-gp) is a multidrug transporter, which harnesses the chemical energy of ATP to power the efflux of diverse chemotherapeutics out of cells and thus contributes to the development of multidrug resistance (MDR) in cancer. It has been proved that the ligand-binding pocket of P-gp is located at the transmembrane domains (TMDs). However, the access of ligands into the binding pocket remains to be elucidated, which definitely hinder the development of P-gp inhibitors. Herein, the access pathways of a well-known substrate rhodamine-123 and a cyclopeptide inhibitor QZ-Leu were characterized by time-independent partial nudged elastic band (PNEB) simulations. The decreasing free energies along the PNEB-optimized access pathway indicated that TM4/6 cleft may be an energetically favorable entrance gate for ligand entry into the binding pocket of P-gp. The results can be reconciled with a range of experimental studies, further corroborating the reliability of the gate revealed by computational simulations. Our atomic level description of the ligand access pathway provides valuable insights into the gating mechanism for drug uptake and transport by P-gp and other multidrug transporters.
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