Biophysical and in silico characterization of the interaction of anticancer drugs with human serum albumin / Salanee Kandandapani
Tyrphostin 9 (Tyr 9), pazopanib (PZP) and regorafenib (REG) are potent platelet-derived growth factor receptor (PDGFR) inhibitors, and induce apoptosis in various cancer cell types such as chronic myeloid leukemia, soft tissue sarcoma, renal cancer, colorectal cancer and gastrointestinal stromal...
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| Format: | Thesis |
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2022
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| Online Access: | http://studentsrepo.um.edu.my/14297/ http://studentsrepo.um.edu.my/14297/2/Salanee.pdf http://studentsrepo.um.edu.my/14297/1/Salanee.pdf |
| Summary: | Tyrphostin 9 (Tyr 9), pazopanib (PZP) and regorafenib (REG) are potent platelet-derived
growth factor receptor (PDGFR) inhibitors, and induce apoptosis in various cancer cell
types such as chronic myeloid leukemia, soft tissue sarcoma, renal cancer, colorectal
cancer and gastrointestinal stromal tumors. The binding of these drugs to the major
transport protein in human circulation, human serum albumin (HSA) was investigated
using fluorescence and UV-vis absorption spectroscopic techniques as well as molecular
docking methods. Fluorescence quenching titration results showed progressive decline in
the protein fluorescence with increasing drug concentrations. A decreasing trend of the
Stern-Volmer constant, Ksv with increasing temperature characterized the drug-induced
quenching as static quenching, thus pointed towards the formation of
Tyr 9/PZP/REG–HSA complexes. This was further confirmed by the hyperchromic effect
seen in the UV-vis absorption spectra of HSA upon addition of these drugs. The
binding constant (Ka) values of these drug–HSA systems were found to lie within the
range 1.29–3.56 × 105 M-1 at 298 K, which suggested moderate binding affinity between
these ligands and HSA. The drug–HSA complexes were found to be stabilized by
hydrophobic interactions, van der Walls forces and hydrogen bonds, based on the
thermodynamic data [(ΔS° = + 13.90 J mol–1 K–1 and ΔH° = – 26.60 kJ mol–1for Tyr 9–
HSA system); (ΔS° = + 98.37 J mol–1 K–1 and ΔH° = – 60.31 kJ mol–1for PZP–HSA
system); (ΔS° = + 17.17 J mol–1 K–1 and ΔH° = – 23.00 kJ mol–1for REG–HSA system)].
These results were further supported by the molecular docking analyses. Interaction of
Tyr 9, PZP and REG with HSA also produced microenvironmental perturbations around
protein fluorophores (Tyr and Trp), as evident from the 3-D fluorescence spectral results but increased protein’s conformational stability against thermal denaturation.
Competitive drug displacement results along with molecular docking analyses suggested
Sudlow’s Site I of HSA as the preferred Tyr 9, PZP and REG binding site.
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