title: The role of positive charges on G-quadruplex binding small molecules: learning from bisaryldiketene derivatives.
abstract: BACKGROUND
  G-quadruplexes are promising therapeutic targets for small molecules. In general, the introduction of steady positive charges through the in situ alkylation of nitrogen atoms within potential G-quadruplex ligands can significantly improve their quadruplex binding and stabilization abilities. However, our previous studies on bisaryldiketene derivatives showed that the derivative M4, whose central piperidone moiety is quaternized, exhibits a poor G-quadruplex stabilization ability.
  
  
  METHODS
  To clarify this unusual finding, CD, ITC, UV and NMR analyses were performed to determine the binding behaviors of M4 and its non-quaternized analog M2 to G-quadruplex DNA [d(TGGGT)]4. Molecular modeling approaches were also employed to help illustrate ligand-quadruplex DNA interactions.
  
  
  RESULTS
  The CD melting and ITC analyses revealed that M2 exhibited much stronger stabilization and binding abilities to [d(TGGGT)]4 compared to M4. Moreover, the CD and ITC analyses in combination with UV, NMR and MD simulations revealed that M2 tended to be end-stacked on the G-quartet, whereas M4 tended to be bound in the groove region. Analysis of the electrostatic potential showed that the charged surface of M4 was more positive than that of M2 and other reported ligands that bind to the G-quadruplex via end-stacking interactions.
  
  
  CONCLUSIONS
  The results indicated that the different positively charged surfaces of M2 and M4 might be the key reason for their different binding modes. These different binding modes also lead to different binding affinities and stabilization abilities for [d(TGGGT)]4.
  
  
  CONCLUSIONS
  These results provide new clues for the rational design of G-quadruplex-binding small molecules with steady positive charges.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Shuo-Bin
authors.initials: SB
authors.lastname: Chen
authors.forename: Qiu-Xia
authors.initials: QX
authors.lastname: Shi
authors.forename: Dan
authors.initials: D
authors.lastname: Peng
authors.forename: Si-Yuan
authors.initials: SY
authors.lastname: Huang
authors.forename: Tian-Miao
authors.initials: TM
authors.lastname: Ou
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.forename: Jia-Heng
authors.initials: JH
authors.lastname: Tan
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
mesh_terms: D002151:Calorimetry / Q000379:methods; D002942:Circular Dichroism / Q000379:methods; D004247:DNA / Q000737:chemistry; D054856:G-Quadruplexes; D007700:Kinetics; D007783:Lactones / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D054852:Small Molecule Libraries / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet / Q000379:methods; D013816:Thermodynamics
chemical_list: D007783:Lactones; D008024:Ligands; D054852:Small Molecule Libraries; C004773:diketene; D004247:DNA
keywords: Biophysical study; Bisaryldiketene derivative; G-quadruplex; Molecular modeling; Positive charge