Title
Quantitative parameters of complexes of tris(1-alkylindol-3-yl)methylium salts with serum albumin: Relevance for the design of drug candidates
Author
Nikita A. Durandin, Vladimir B. Tsvetkov, Evgeny E. Bykov, Dmitry N. Kaluzhny, Sergey N. Lavrenov, Anna N. Tevyashova, Maria N. Preobrazhenskaya
Year
2016
Journal
Journal of Photochemistry and Photobiology B: Biology
Abstract
Triarylmethane derivatives are extensively investigated as antitumor and antibacterial drug candidates alone and as photoactivatable compounds. In the series of tris(1-alkylindol-3-yl)methylium salts (TIMs) these two activities differed depending on the length of N-alkyl chain, with C4–5 derivatives being the most potent compared to the shorter or longer chain analogs and to the natural compound turbomycin A (no N-substituent). Given that the human serum albumin (HSA) is a major transporter protein with which TIMs can form stable complexes, and that the formation of these complexes might be advantageous for phototoxicity of TIMs we determined the quantitative parameters of TIM-HSA binding using spectroscopic methods and molecular docking. TIMs bound to HSA (1:1 stoichiometry) altered the protein's secondary structure by changing the α-helix/β-turn ratio. The IIa subdomain (Sudlow site I) is the preferred TIM binding site in HSA as determined in competition experiments with reference drugs ibuprofen and warfarin. The values of binding constants increased with the number of CH2 groups from 0 to 6 and then dropped down for C10 compound, a dependence similar to the one observed for cytocidal potency of TIMs. We tend to attribute this non-linear dependence to an interplay between hydrophobicity and steric hindrance, the two key characteristics of TIM-HSA complexes calculated in the molecular docking procedure. These structure-activity relationships provide evidence for rational design of TIM-based antitumor and antimicrobial drugs.
Instrument
J-715
Keywords
Circular dichroism, Secondary structure, Ligand binding, Biochemistry, Pharmaceutical