Department of Chemistry, College of Science, Yanbian University, Yanji, PR China.
Bioorg Med Chem Lett. 2011 Dec 1;21(23):6969-72. doi: 10.1016/j.bmcl.2011.09.125. Epub 2011 Oct 5.
DNA G-quadruplex is an attractive drug target for anticancer therapy. Most G-quadruplex ligands have little selectivity, due to π-stacking interaction with common G-tetrads surface. Thanks to the varieties of G-quadruplex grooves, the groove-binding ligand is expected to create high selectivity. Therefore, developing novel molecular geometries that target G-quadruplex groove has been paid growing attention. In this work, steroid FG, a special nonplanar and nonaromatic small molecule, interacting with different conformations of G-quadruplexes has been studied by molecular docking and molecular dynamics simulations. The results showed the selectivity of the hydrophobic group of steroid FG for the wide groove of antiparallel G-quadruplex. The methyl groups on the tetracyclic ring of steroid represent the specific binding ability for the small hydrophobic cavity formed by reversed stacking of G-tetrads in antiparallel G-quadruplex groove. This work provides new insight for developing new classes of G-quadruplex groove-binding ligands.
DNA 四链体是一种有吸引力的抗癌治疗药物靶点。由于与常见的 G-四联体表面的π堆积相互作用，大多数 G-四联体配体选择性很小。由于 G-四链体沟槽的多样性，沟槽结合配体有望产生高选择性。因此，开发靶向 G-四链体沟槽的新型分子几何形状受到了越来越多的关注。在这项工作中，通过分子对接和分子动力学模拟研究了甾族 FG，一种特殊的非平面非芳香小分子，与不同构象的 G-四链体的相互作用。结果表明，甾族 FG 的疏水区基团对反平行 G-四链体的宽沟具有选择性。甾族四环上的甲基代表了与反平行 G-四链体沟槽中 G-四联体反向堆积形成的小疏水性腔的特异性结合能力。这项工作为开发新型 G-四链体沟槽结合配体提供了新的见解。
