Journal
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Volume 61, Issue 1, Pages 252-262Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.0c00892
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Funding
- National Natural Science Foundation of China [81904198]
- Science and Technology Planning Project of Guangdong Province [2017B030314166]
- Guangxi University of TCM's Introduction of Doctor Scientific Research Startup Fund [B170019]
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The study investigated the inhibitory effect of (+)-borneol and (-)-borneol on P-glycoprotein (Pgp) in reversing mitoxantrone (MTO) resistance. The results showed that both borneol enantiomers could enhance the efficacy of MTO in cancer cells by reducing the protein expression of Pgp and interfering with the binding affinity between MTO and Pgp in the drug-binding pocket. Using molecular docking and dynamics simulations, the study identified key amino acid residues responsible for borneols' ability to reverse MTO resistance through noncompetitive inhibition.
P-Glycoprotein (Pgp) is a main factor contributing to multidrug resistance and the consequent failure of chemotherapy. Overcoming Pgp efflux is a strategy to improve the efficacy of drugs. (+)-Borneol (BNL1) and (-)-borneol (BNL2) interfere and inhibit Pgp, and thus, the accumulation of drugs increases in cells. However, it is not clear yet how they play the inhibitory effect against Pgp. In this work, the effect and molecular mechanism of borneol enantiomers in reversing mitoxantrone (MTO) resistance against Pgp were explored by in vitro and in silico approaches. Chemosensitizing potential tests showed that BNLs could enhance the efficacy of MTO in MES-SA/MX2 cells, and BNL2 exhibited a stronger potential. The protein expression of Pgp was decreased to some extent by the administration of BNLs. Molecular docking revealed that BNLs could reduce the binding affinity between MTO and Pgp. The results were consistent with the chemosensitizing potential test and were supported by molecular dynamics (MD) simulations. Molecular docking also suggested that BNLs preferred to bind in the drug-binding pocket rather than the nucleotide-binding domain of inward-facing Pgp. The occupied space of BNLs had an evident distance from that of MTO, which was further verified by the conformational analysis after MD simulations. The decomposition of binding free energies revealed the key amino acid residues (GLN19S, SER196, TRP232, PHE343, SER344, GLY346, and GLN347) for BNLs to reverse MTO resistance. The results provide an insight into the mechanism through which BNLs reduce the MTO resistance against inward-facing Pgp in the drug-binding pocket through noncompetitive inhibition.
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