Molecular insights into the selective binding mechanism targeting parallel human telomeric G-quadruplex

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Stabilizing human telomere DNA G-quadruplex (G4) structures is a promising anti-cancer approach.
• Understanding the selective binding mechanisms of G4-stabilizing molecules is crucial for drug development.
• Previous research identified a monohydrazone derivative (compound 15) with a preference for parallel human telomeric G4.

Purpose of the Study:

• To elucidate the selective binding mechanism of monohydrazone derivatives with different telomeric G4 conformations.
• To investigate the preferred binding modes and the factors influencing binding affinity.
• To provide atomic-level insights for designing more selective G4 stabilizers.

Main Methods:

• Comparative theoretical investigation of two monohydrazone derivatives (compounds 1 and 15) and three telomeric G4 conformations (parallel, hybrid-I, hybrid-II).
• Molecular docking to predict potential binding modes (end-stacking and groove binding).
• Long-timescale molecular dynamics simulations and binding free energy calculations.

Main Results:

• Both compounds showed a preference for the end-stacking binding mode over groove binding.
• Van der Waals interactions were identified as the primary driver of binding affinity.
• The parallel G4-compound 15 complex exhibited the highest binding affinity and strongest stabilizing effect, consistent with experimental data.

Conclusions:

• Compound 15 demonstrates selective binding and stabilization of parallel human telomeric G4 through end-stacking interactions.
• Van der Waals forces are critical for achieving selective binding and high affinity.
• These findings support the rational design of novel, selective G4 stabilizers for cancer therapy.