title: Quantitative parameters of complexes of tris(1-alkylindol-3-yl)methylium salts with serum albumin: Relevance for the design of drug candidates.
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 TIMs-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 TIMs-HSA complexes calculated in the molecular docking procedure. These structure-activity relationships provide evidence for rational design of TIMs-based antitumor and antimicrobial drugs.
authors.affiliation: Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 4 Kosygin Street, Moscow 119334, Russia. Electronic address: nikita.durandin@gmail.com.
authors.forename: Nikita A
authors.initials: NA
authors.lastname: Durandin
authors.affiliation: Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 29 Leninsky Prospect, Moscow 119991, Russia; Research Institute of Physical-Chemical Medicine, 1a M. Pirogovskaya Street, Moscow 119992, Russia. Electronic address: v.b.svetkov@gmail.com.
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Tsvetkov
authors.affiliation: Gause Institute of New Antibiotics, Russian Academy of Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
authors.forename: Evgeny E
authors.initials: EE
authors.lastname: Bykov
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia.
authors.forename: Dmitry N
authors.initials: DN
authors.lastname: Kaluzhny
authors.affiliation: Gause Institute of New Antibiotics, Russian Academy of Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Lavrenov
authors.affiliation: Gause Institute of New Antibiotics, Russian Academy of Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russia; National University of Science and Technology "MISIS", 2 Leninsky Prospect, Moscow 119049, Russia.
authors.forename: Anna N
authors.initials: AN
authors.lastname: Tevyashova
authors.affiliation: Gause Institute of New Antibiotics, Russian Academy of Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Preobrazhenskaya
mesh_terms: D001665:Binding Sites; D002942:Circular Dichroism; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry / Q000378:metabolism; D007211:Indoles / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012492:Salts / Q000737:chemistry; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics; D014859:Warfarin / Q000737:chemistry / Q000378:metabolism
chemical_list: D007211:Indoles; D012492:Salts; D012709:Serum Albumin; C466303:turbomycin A; D014859:Warfarin; C030374:indole; D007052:Ibuprofen
keywords: Human serum albumin; Molecular docking; Spectroscopy; Triarylmethane dyes; Triindolylmethane derivatives