Selective Targeting of G-Quadruplex Structures by a Benzothiazole-Based Binding Motif

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Molecular Biology

Background:

• DNA G-quadruplexes are non-canonical DNA structures implicated in various biological processes.
• Targeting G-quadruplexes with small molecules offers therapeutic potential for diseases like cancer.
• Benzothiazole derivatives are a class of compounds with diverse biological activities.

Purpose of the Study:

• To identify and characterize a novel benzothiazole derivative as a ligand for DNA G-quadruplexes.
• To investigate the binding selectivity and mechanism of the ligand towards different G-quadruplex topologies.
• To provide structural and thermodynamic insights into ligand-G-quadruplex interactions for rational drug design.

Main Methods:

• Fluorescence titrations to assess binding affinity and selectivity.
• Spectroscopic techniques (UV-Vis, fluorescence) for interaction studies.
• Isothermal titration calorimetry (ITC) for thermodynamic profiling.
• Nuclear Magnetic Resonance (NMR) spectroscopy for structural characterization.
• Mass spectrometry for determining complex stoichiometry.

Main Results:

• A benzothiazole derivative was identified as a potent ligand for DNA G-quadruplexes.
• The ligand exhibited selective binding towards parallel, antiparallel, and hybrid G-quadruplex structures.
• The parallel c-MYC G-quadruplex was the preferred target, with dissociation constants in the micromolar range.
• Ligand binding involved 1:1 and 2:1 stoichiometries and induced significant structural rearrangements.
• Enthalpic contributions were identified as the primary driving force for ligand-G-quadruplex association.

Conclusions:

• Benzothiazole derivatives can act as effective ligands for DNA G-quadruplexes.
• The identified ligand demonstrates promising selectivity for specific G-quadruplex topologies, notably the c-MYC sequence.
• Detailed structural and thermodynamic characterization provides a foundation for developing advanced benzothiazole-based G-quadruplex binders.