Target fishing of glycopentalone using integrated inverse docking and reverse pharmacophore mapping approach.
Target fishing of glycopentalone using integrated inverse docking and reverse pharmacophore mapping approach.
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DOI：
10.4238/gmr.15038544
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发表时间：
2016-08
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通讯作者：
A. Gurung;M. A. Ali;Atanu Bhattacharjee;K. Al-Anazi;M. Farah;F. Al-Hemaid;F. Abou-Tarboush;Joongku Lee;Soo-Yong Kim;F. Al-Anazi
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作者：
A. Gurung;M. A. Ali;Atanu Bhattacharjee;K. Al-Anazi;M. Farah;F. Al-Hemaid;F. Abou-Tarboush;Joongku Lee;Soo-Yong Kim;F. Al-Anazi
从十字花科植物绞股蓝中分离得到的糖酯类化合物对多种人类癌细胞具有细胞毒作用和诱导细胞凋亡作用，但其作用机制尚不清楚。因此，我们采用反向对接和反向药效团作图相结合的方法对糖蛋白进行靶点筛选，以确定糖蛋白的潜在靶点，并深入了解其与CDK-2、CDK-6、拓扑异构酶I、Bcl-2、VEGFR-2、端粒：G-四链体和拓扑异构酶II等分子靶点的结合模式。这些靶点是基于它们在细胞周期和DNA复制调控肿瘤进展中的关键作用而选择的。分子对接分析表明，糖蛋白与靶标的结合能为-6.38~-8.35kcal/μ，抑制常数为0.758~20.90 kcal M。糖蛋白与靶分子的亲和力顺序为：端粒：G-四链和GT；VEGFR-2和GT；CDK-6和GT；CDK-2和GT；拓扑异构酶II和GT；拓扑异构酶I和GT；Bcl2。结合模式分析揭示了临界氢键以及与靶的疏水相互作用。这些靶点通过糖基端酮与一组2241个已知的人类靶蛋白的反向药效团图谱进行了验证，这些蛋白质显示CDK-2和VEGFR-2是最有利的靶点。糖基戊酮与CDK-2和VEGFR-2有很好的对应关系，分别涉及6个药效团特征(2个疏水中心和4个氢键受体)和9个药效团特征(5个疏水中心、2个氢键受体和2个氢键供体)。目前的计算方法可能有助于在生物检测验证之前针对大量候选大分子合理地识别小分子的靶标。
Glycopentalone isolated from Glycosmis pentaphylla (family Rutaceae) has cytotoxic and apoptosis inducing effects in various human cancer cell lines; however, its mode of action is not known. Therefore, target fishing of glycopentalone using a combined approach of inverse docking and reverse pharmacophore mapping approach was used to identify potential targets of glycopentalone, and gain insight into its binding modes against the selected molecular targets, viz., CDK-2, CDK-6, Topoisomerase I, Bcl-2, VEGFR-2, Telomere:G-quadruplex and Topoisomerase II. These targets were chosen based on their key roles in the progression of cancer via regulation of cell cycle and DNA replication. Molecular docking analysis revealed that glycopentalone displayed binding energies ranging from -6.38 to -8.35 kcal/mol and inhibition constants ranging from 0.758 to 20.90 μM. Further, the binding affinities of glycopentalone to the targets were in the order: Telomere:G-quadruplex > VEGFR-2 > CDK-6 > CDK-2 > Topoisomerase II > Topoisomerase I > Bcl-2. Binding mode analysis revealed critical hydrogen bonds as well as hydrophobic interactions with the targets. The targets were validated by reverse pharmacophore mapping of glycopentalone against a set of 2241 known human target proteins which revealed CDK-2 and VEGFR-2 as the most favorable targets. The glycopentalone was well mapped to CDK-2 and VEGFR-2 which involve six pharmacophore features (two hydrophobic centers and four hydrogen bond acceptors) and nine pharmacophore features (five hydrophobic, two hydrogen bond acceptors and two hydrogen bond donors), respectively. The present computational approach may aid in rational identification of targets for small molecules against large set of candidate macromolecules before bioassays validation.