Rational Discovery of Dengue Type 2 Non-Competitive Inhibitors
Rational Discovery of Dengue Type 2 Non-Competitive Inhibitors
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DOI：
10.1111/cbdd.12122
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发表时间：
2013-07-01
影响因子：
3
通讯作者：
Rahman, Noorsaadah A.
中科院分区：
文献类型：
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作者：
Heh, Choon H.;Othman, Rozana;Rahman, Noorsaadah A.
在开发针对登革热的治疗方法方面开展了各种工作。然而，迄今为止，尚未发现有效的疫苗或抗登革热剂。蛋白酶抑制剂的开发被认为是一个有前途的选择，但大多数先前的工作都涉及竞争性抑制。在本研究中，我们的重点是基于DEN-2 NS2B/NS3蛋白酶的非竞争性抑制，合理发现潜在的抗登革热药物。以western Nile Virus NS2B/NS3蛋白酶复合物2FP7为模板构建的DEN-2 NS2B/NS3蛋白酶同源模型为靶标，以黄酮pinostrobin为标准配体。虚拟筛选涉及13341个小化合物，主要结构为查尔酮、黄酮和黄酮，可从锌数据库中获得。对所得到的化合物进行排序，得到了与标准配体相比具有更高结合亲和力的化合物。结果表明，对den2 NS2B/NS3蛋白水解活性的抑制作用明显优于对照，且与体外实验结果具有良好的相关性。总之，通过这种理性发现技术，发现了更好的抑制剂。该方法可用于进一步发现抗登革热药物的先导化合物。
Various works have been carried out in developing therapeutics against dengue. However, to date, no effective vaccine or anti-dengue agent has yet been discovered. The development of protease inhibitors is considered as a promising option, but most previous works have involved competitive inhibition. In this study, we focused on rational discovery of potential anti-dengue agents based on non-competitive inhibition of DEN-2 NS2B/NS3 protease. A homology model of the DEN-2 NS2B/NS3 protease (using West Nile Virus NS2B/NS3 protease complex, 2FP7, as the template) was used as the target, and pinostrobin, a flavanone, was used as the standard ligand. Virtual screening was performed involving a total of 13341 small compounds, with the backbone structures of chalcone, flavanone, and flavone, available in the ZINC database. Ranking of the resulting compounds yielded compounds with higher binding affinities compared with the standard ligand. Inhibition assay of the selected top-ranking compounds against DEN-2 NS2B/NS3 proteolytic activity resulted in significantly better inhibition compared with the standard and correlated well with in silico results. In conclusion, via this rational discovery technique, better inhibitors were identified. This method can be used in further work to discover lead compounds for anti-dengue agents.