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  3. Insights into interactions between taxanes and P-glycoprotein using biophysical and in silico methods

Insights into interactions between taxanes and P-glycoprotein using biophysical and in silico methods

  • J Pharm Sci. 2025 Feb 25;114(5):103708. doi: 10.1016/j.xphs.2025.103708.
Longwen Xu 1,  Katherine G Schaefer 2,  Gavin M King 3,  Zhong-Ru Xie 4,  Michael G Bartlett 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, USA.
  • 2 Department of Physics and Astronomy, University of Missouri, Columbia, MO 65211, USA.
  • 3 Department of Physics and Astronomy, University of Missouri, Columbia, MO 65211, USA; Joint with Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA.
  • 4 Computational Drug Discovery Laboratory, School of Electrical and Computer Engineering, College of Engineering, University of Georgia, Athens, GA 30602, USA.
  • 5 Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, USA. Electronic address: mgbart@uga.edu.
PMID: 40015511 DOI: 10.1016/j.xphs.2025.103708
Abstract

Multidrug resistance mediated by P-glycoprotein (Pgp) is a significant obstacle to Cancer chemotherapy. Taxane drugs, including paclitaxel, docetaxel, and cabazitaxel, are used to treat multiple types of Cancer. All taxane drugs are Pgp substrates, but cabazitaxel is also a Pgp inhibitor, indicating potential differential interactions between Pgp and different taxanes. Here, we showed for the first time that cabazitaxel had a partial inhibitory effect on the ATPase activity at concentrations higher than 10 µM. We found the KD of paclitaxel, docetaxel, and cabazitaxel to Pgp are 0.85 µM, 40.59 µM, and 13.53 µM, respectively. Based on acrylamide quenching, paclitaxel induced Pgp into a wide inward-facing open conformation at a high concentration but a slightly occluded conformation at lower concentrations. Both docetaxel and cabazitaxel shifted Pgp towards occluded states, each drug resulting in a unique degree of occlusion. Furthermore, molecular docking and energy calculations revealed that cabazitaxel binds with the "access tunnel" and blocks the subsequent nucleotide-binding domain dimerization. Our results indicate that the preference of taxanes for different binding sites on Pgp leads to distinct transport mechanisms. These results provide valuable insight into the interaction between taxanes and Pgp, which will enhance future drug development.

Keywords

Cancer chemotherapy; Fluorescence spectroscopy; In silico modeling; Multidrug resistance; P-glycoprotein.

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