title: Breast anticancer drug tamoxifen and its metabolites bind tRNA at multiple sites.
abstract: The binding sites of breast anticancer drug tamoxifen and its metabolites with tRNA were located by FTIR, CD, UV-visible, and fluorescence spectroscopic methods and molecular modeling. Structural analysis showed that tamoxifen and its metabolites bind tRNA at several binding sites with overall binding constants of K(tam-tRNA) = 5.2 (± 0.6) × 10(4) M(-1), K(4-hydroxytam-tRNA) = 6.5 ( ± 0.5) × 10(4) M(-1) and K(endox-tRNA) = 1.3 (± 0.2) × 10(4) M(-1). The number of binding sites occupied by drug molecules on tRNA were 1 (tamoxifen), 0.8 (4-hydroxitamoxifen) and 1.2 (endoxifen). Docking showed the participation of several nucleobases in drug-tRNA complexes with the free binding energy of -4.31 (tamoxifen), -4.45 (4-hydroxtamoxifen) and -4.38 kcal/mol (endoxifen). The order of binding is 4-hydroxy-tamoxifen > tamoxifen > endoxifen. Drug binding did not alter tRNA conformation from A-family structure, while biopolymer aggregation occurred at high drug concentration.
authors.affiliation: Department of Chemistry-Physics, University of Québec in Trois-Rivières, C. P. 500, Trois-Rivières, Québec G9A 5H7, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Bourassa
authors.affiliation: Department of Medicine, Rutgers Robert Wood Johnson Medical School, and Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Thomas
authors.affiliation: Division of Humanities: Math/Sciences, University of Hawaii-West O'ahu, 91-1001 Farrington Highway, Kapolei, HI 96707, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bariyanga
authors.affiliation: Department of Chemistry-Physics, University of Québec in Trois-Rivières, C. P. 500, Trois-Rivières, Québec G9A 5H7, Canada. Electronic address: tajmirri@uqtr.ca.
authors.forename: H A
authors.initials: HA
authors.lastname: Tajmir-Riahi
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002942:Circular Dichroism; D005260:Female; D006801:Humans; D009690:Nucleic Acid Conformation / Q000187:drug effects; D012343:RNA, Transfer / Q000737:chemistry* / Q000187:drug effects; D013050:Spectrometry, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared; D013629:Tamoxifen / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D013629:Tamoxifen; D012343:RNA, Transfer
keywords: 4-hydroxtamox4-hydroxytamoxifen; Binding site; CDcircular dichroism; FTIRFourier transform infrared spectroscopy; Modeling; Spectroscopy; Tamoxifen; endoxendoxifen; tRNA; tamoxtamoxifen