Structural Insights into the Interactions of Ligand and G-quadruplez
A new series of quinazoline derivatives were designed, synthesized and evaluated as selective telomeric G-quadruplex binding ligands against the duplex DNA. Circular dichroism (CD) studies showed that these compounds bound in the telomeric G-quadruplex with a 4:1 stoichiometry, thus indicating they recognized the quadruplex via multiple binding modes. To further gain insight into the nature of the interactions of derivatives with telomeric G-quadruplex DNA, an approach that combined molecular docking, molecular dynamics (MD) simulations, and evaluation of binding affinity was performed1. Docking studies showed that the ligands could bind to the hybrid-type G-quadruplex structure (PDB 2HY92) in both end-stacking and groove binding modes. Based upon the CD and docking results, molecular dynamics simulations of a 4:1 ligand-quadurplex complex were progressed. The estimated free energy of binding using MM/PBSA method was —175.4 kJ/mol for the ligands in four binding sites (Figure 1). In conclusion, our research might provide useful information for the further design of selective quadruplex ligands with multiple binding modes. The softwares used in this work were Discovery Studio2.0, Gaussian 03, autodock 4.0, and amber 10.
Jin-Qiang Hou Jia-Heng Tan Zhi-Shu Huang Lian-Quan Gu
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
国际会议
广州
英文
544-544
2008-11-01（万方平台首次上网日期，不代表论文的发表时间）