Binding of berberine derivates to G-quadruplex: insight from a computational study

Area of Science:

• Computational Chemistry
• Molecular Biology
• Pharmacology

Background:

• Human telomerase activity in cancer cells drives immortal proliferation.
• Stabilizing G-quadruplex DNA structures is a potential anti-cancer therapy strategy.
• Berberine (BER) and its derivatives show potential for G-quadruplex stabilization.

Purpose of the Study:

• To investigate atomic interactions between G-quadruplexes and Berberine (BER) and its derivatives.
• To evaluate the efficacy of BER derivatives as G-quadruplex stabilizers for anti-cancer therapy.
• To provide atomic-level insights into G-quadruplex-ligand binding.

Main Methods:

• Molecular dynamics simulations were employed to model G-quadruplex-ligand interactions.
• Various force fields and charge models were tested for accurate simulation of charged nucleic acids.
• Binding energies were calculated using molecular mechanics/generalized Born surface area and interaction entropy methods.

Main Results:

• Simulations showed G-quadruplex stability increased in the presence of BER and derivatives.
• BER derivatives exhibited higher binding affinity to G-quadruplexes than BER.
• The first G-tetrad was identified as crucial for binding, with van der Waals interactions being most favorable.

Conclusions:

• Berberine derivatives offer a promising therapeutic strategy by stabilizing G-quadruplexes.
• Atomic-level insights into G-quadruplex-inhibitor interactions guide future drug design.
• These findings contribute to developing novel anti-cancer agents targeting G-quadruplex DNA.