Structure–Function Relationships in the Human P-Glycoprotein (ABCB1): Insights from Molecular Dynamics Simulations

International Journal of Molecular Sciences

卷:23

Yunierkis Pérez-Castillo¹  Liadys Mora Lagares²  Nikola Minovski²  Marjana Novič² 

[1] Bio-Cheminformatics Research Group and Escuela de Ciencias Físicas y Matemáticas, Universidad de Las Américas, Quito 170513, Ecuador;

[2] Theory Department, Laboratory for Cheminformatics, National Institute of Chemistry, 1000 Ljubljana, Slovenia;

关键词: P-Glycoprotein;    molecular dynamics simulations;    ABC transporter;    multidrug resistance (MDR);    conformational changes;   

DOI  :  10.3390/ijms23010362

来源: DOAJ

【 摘 要 】

P-Glycoprotein (P-gp) is a transmembrane protein belonging to the ATP binding cassette superfamily of transporters, and it is a xenobiotic efflux pump that limits intracellular drug accumulation by pumping compounds out of cells. P-gp contributes to a reduction in toxicity, and has broad substrate specificity. It is involved in the failure of many cancer and antiviral chemotherapies due to the phenomenon of multidrug resistance (MDR), in which the membrane transporter removes chemotherapeutic drugs from target cells. Understanding the details of the ligand–P-gp interaction is therefore critical for the development of drugs that can overcome the MDR phenomenon, for the early identification of P-gp substrates that will help us to obtain a more effective prediction of toxicity, and for the subsequent outdesign of substrate properties if needed. In this work, a series of molecular dynamics (MD) simulations of human P-gp (hP-gp) in an explicit membrane-and-water environment were performed to investigate the effects of binding different compounds on the conformational dynamics of P-gp. The results revealed significant differences in the behaviour of P-gp in the presence of active and non-active compounds within the binding pocket, as different patterns of movement were identified that could be correlated with conformational changes leading to the activation of the translocation mechanism. The predicted ligand–P-gp interactions are in good agreement with the available experimental data, as well as the estimation of the binding-free energies of the studied complexes, demonstrating the validity of the results derived from the MD simulations.

【 授权许可】

Unknown