Binding of berberine derivates to G-quadruplex: insight from a computational study
PHYSICAL CHEMISTRY CHEMICAL PHYSICS(2023)
摘要
Human telomerase exhibits significant activity in cancer cells relative to normal cells, which contributes to the immortal proliferation of cancer cells. To counter this, the stabilization of G-quadruplexes formed in the guanine-rich sequence of the cancer cell chromosome has emerged as a promising avenue for anti-cancer therapy. Berberine (BER), an alkaloid that is derived from traditional Chinese medicines, has shown potential for stabilizing G-quadruplexes. To investigate the atomic interactions between G-quadruplexes and BER and its derivatives, molecular dynamics simulations were conducted. Modeling the interactions between G-quadruplexes and ligands accurately is challenging due to the strong negative charge of nucleic acids. Thus, various force fields and charge models for the G-quadruplex and ligands were tested to obtain precise simulation results. The binding energies were calculated by a combination of molecular mechanics/generalized Born surface area and interaction entropy methods, and the calculated results correlated well with experimental results. B-factor and hydrogen bond analyses demonstrated that the G-quadruplex was more stable in the presence of ligands than in the absence of ligands. Calculation of the binding free energy showed that the BER derivatives bind to a G-quadruplex with higher affinity than that of BER. The breakdown of the binding free energy to per-nucleotide energies suggested that the first G-tetrad played a primary role in binding. Additionally, energy and geometric properties analyses indicated that van der Waals interactions were the most favorable interactions between the derivatives and the G-quadruplexes. Overall, these findings provide crucial atomic-level insights into the binding of G-quadruplexes and their inhibitors.
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关键词
berberine derivates,g-quadruplex
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