Dipartimento di Scienze della Salute, Università degli Studi "Magna Græcia", Campus "S. Venuta", Viale Europa, Germaneto, Catanzaro 88100, Italy.
Molecules. 2013 Sep 30;18(10):12051-70. doi: 10.3390/molecules181012051.
The G-quadruplex DNA structures are mainly present at the terminal portion of telomeres and can be stabilized by ligands able to recognize them in a specific manner. The recognition process is usually related to the inhibition of the enzyme telomerase indirectly involved and over-expressed in a high percentage of human tumors. There are several ligands, characterized by different chemical structures, already reported in the literature for their ability to bind and stabilize the G-quadruplex structures. Using the structural and biological information available on these structures; we performed a high throughput in silico screening of commercially natural compounds databases by means of a structure-based approach followed by docking experiments against the human telomeric sequence d[AG₃(T₂AG₃)₃]. We identified 12 best hits characterized by different chemical scaffolds and conformational and physicochemical properties. All of them were associated to an improved theoretical binding affinity with respect to that of known selective G-binders. Among these hits there is a chalcone derivative; structurally very similar to the polyphenol butein; known to remarkably inhibit the telomerase activity.
G-四链体 DNA 结构主要存在于端粒的末端部分，可以通过能够以特定方式识别它们的配体来稳定。识别过程通常与间接抑制参与其中的端粒酶有关，而端粒酶在很大比例的人类肿瘤中过度表达。已经有几种配体在文献中被报道，具有结合和稳定 G-四链体结构的能力，它们具有不同的化学结构。利用这些结构的结构和生物学信息；我们通过结构基础方法对商业天然化合物数据库进行了高通量的计算机筛选，然后针对人类端粒序列 d[AG₃(T₂AG₃)₃]进行对接实验。我们鉴定了 12 个具有不同化学支架和构象和物理化学性质的最佳命中。它们都与已知选择性 G-结合物相比具有改善的理论结合亲和力。在这些命中中，有一个查尔酮衍生物；结构上与多酚紫檀芪非常相似，已知能显著抑制端粒酶活性。
