Interaction between Human Telomere and a Carbazole Derivative: A Molecular Dynamics Simulation of a Quadruplex Stabilizer and Telomerase Inhibitor
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- 作者：Dah-Yen Yang ; Ta-Chau Chang ; and ; Sheh-Yi Sheu ; S.-Y. Sheu
- 刊名：Journal of Physical Chemistry A
- 出版年：2007
- 出版时间：September 27, 2007
- 年：2007
- 卷：111
- 期：38
- 页码：9224 - 9232
- 全文大小：861K
- 年卷期：v.111,no.38(September 27, 2007)
- ISSN：1520-5215
文摘
The mechanism of inhibition of telomerase by drugs is a key factor in an understanding of guanine-quadruplexcomplex stabilization during human cancer. This study describes a simulated annealing docking and moleculardynamics simulation to investigate a synthesized potent inhibitor, 3,6-bis(1-methyl-4-vinylpyridinium iodine)carbazole (BMVC), which stabilizes the quadruplex structure of the human telomeric DNA sequenced[AG3(T2AG3)3] and inhibits telomerase activity. The compound was predicted to selectively interact withthe quadruplex structure. During our simulation, the binding affinities were calculated and used to predict thebest drug-binding sites as well as enhanced selectivity compared with other compounds. Our studies suggestthat the simulation results quite coincide with the experimental results. In addition, molecular modelingshows that a 2:1 binding model involving the external binding of BMVC to both ends of the G-quartet ofd[AG3(T2AG3)3] is the most stable binding mode and this agrees with the absorbance titration results thatshow two binding sites. Of particular interest is that one pyridinium ring and carbazole moiety of the BMVCcan stack well at the end of G-quartet. This implies that BMVC is a good human quadruplex stabilizer andalso a good telomerase inhibitor.