Abstract
Trametinib is a novel anticancer drug for treating metastatic cutaneous melanoma. The present study probed into the binding of trametinib to human serum albumin (HSA) through spectroscopy methods and molecular simulations. Trametinib could quench the fluorescence of HSA through static quenching which could be probed via fluorescence spectroscopy and time-resolved fluorescence. Thermodynamic parameters and docking results indicated that hydrogen bonds and van der Waals forces play crucial roles in this binding process, which exerts almost no effect on the HSA conformation under synchronous fluorescence, three-dimensional fluorescence, circular dichroism spectra, and molecular dynamics simulations. Site marker displacement experiments and molecular docking reveal that trametinib primarily binds to Sudlow site I of HSA. In addition, the trametinib–HSA interaction was hardly influenced by varying amino acid (glutamine, alanine, glycine, and valine) concentrations. This study can provide useful information for the pharmacokinetic properties of trametinib.
Highlights
Trametinib (GSK 1120212) is a novel anticancer drug for treating metastatic cutaneous melanoma.[1,2,3] It was the earliest listed mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor worldwide and was rst approved by the United States Food and Drug Administration in May 2013.4–6 Trametinib was developed for different cancer types, such as biliary tract cancer, rectal cancer, and metastatic breast cancer.[7]Trametinib is present mainly in the form of binding with plasma proteins in the blood because of its high binding rate to plasma protein (97.4%)
Molecular dynamics simulations were applied to investigate the state of the trametinib–human serum albumin (HSA) complex in solution and possible structural changes of HSA induced by trametinib insertion
This result indicated that trametinib binds to HSA
Summary
Trametinib (GSK 1120212) is a novel anticancer drug for treating metastatic cutaneous melanoma.[1,2,3] It was the earliest listed mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor worldwide and was rst approved by the United States Food and Drug Administration in May 2013.4–6 Trametinib was developed for different cancer types, such as biliary tract cancer, rectal cancer, and metastatic breast cancer.[7]. Investigating the characteristics of drugs binding to HSA can contribute to an understanding of the pharmacokinetic properties of drugs in the body.[17,18,19] The interaction between trametinib and HSA has not been reported to date. The trametinib–HSA interaction was explored through several spectroscopy methods, molecular docking, and molecular dynamics simulations. To determine the main binding site of HSA for trametinib, site marker displacement experiments, along with docking so ware were used. Molecular dynamics simulations were applied to investigate the state of the trametinib–HSA complex in solution and possible structural changes of HSA induced by trametinib insertion. The concentrations of circulating amino acids are different and varied in cancer patients, which may affect trametinib binding to HSA. The effects of amino acids on the trametinib– HSA interaction were studied
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