tRNA binding to antitumor drug doxorubicin and its analogue.
The binding sites of antitumor drug doxorubicin (DOX) and its analogue N-(trifluoroacetyl) doxorubicin (FDOX) with tRNA were located, using FTIR, CD, fluorescence spectroscopic methods and molecular modeling. Different binding sites are involved in drug-tRNA adducts with DOX located in the vicinity of A-29, A-31, A-38, C-25, C-27, C-28, G-30 and U-41, while FDOX bindings involved A-23, A-44, C-25, C-27, G-24, G-42, G-53, G-45 and U-41 with similar free binding energy (-4.44 for DOX and -4.41 kcal/mol for FDOX adducts). Spectroscopic results showed that both hydrophilic and hydrophobic contacts are involved in drug-tRNA complexation and FDOX forms more stable complexes than DOX with K DOX-tRNA=4.7 (± 0.5)× 10(4) M(-1) and K FDOX-tRNA=6.3 (± 0.7)× 10(4) M(-1). The number of drug molecules bound per tRNA (n) was 0.6 for DOX and 0.4 for FDOX. No major alterations of tRNA structure were observed and tRNA remained in A-family conformation, while biopolymer aggregation and particle formation occurred at high drug concentrations.
Department of Chemistry and Physics, University of Québec at Trois-Rivières, Trois-Rivières, Québec, Canada.
Daniel
D
Agudelo
Philippe
P
Bourassa
Marc
M
Beauregard
Gervais
G
Bérubé
Heidar-Ali
HA
Tajmir-Riahi
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D002942:Circular Dichroism; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D062105:Molecular Docking Simulation; D009690:Nucleic Acid Conformation; D020871:RNA Stability; D012343:RNA, Transfer / Q000737:chemistry / Q000378:metabolism*; D012265:Ribonucleotides / Q000737:chemistry; D012996:Solutions; D013050:Spectrometry, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared; D013816:Thermodynamics
D000970:Antineoplastic Agents; D012265:Ribonucleotides; D012996:Solutions; D004317:Doxorubicin; D012343:RNA, Transfer