Swiss Institute of Bioinformatics and Biozentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
J Med Chem. 2010 Feb 25;53(4):1483-95. doi: 10.1021/jm900776m.
Dengue fever is a viral disease that affects 50-100 million people annually and is one of the most important emerging infectious diseases in many areas of the world. Currently, neither specific drugs nor vaccines are available. Here, we report on the discovery of new inhibitors of the viral NS5 RNA methyltransferase, a promising flavivirus drug target. We have used a multistage molecular docking approach to screen a library of more than 5 million commercially available compounds against the two binding sites of this enzyme. In 263 compounds chosen for experimental verification, we found 10 inhibitors with IC(50) values of <100 microM, of which four exhibited IC(50) values of <10 microM in in vitro assays. The initial hit list also contained 25 nonspecific aggregators. We discuss why this likely occurred for this particular target. We also describe our attempts to use aggregation prediction to further guide the study, following this finding.
登革热是一种病毒性疾病，每年影响 5000 万至 1 亿人，是世界许多地区最重要的新发传染病之一。目前，既没有特定的药物，也没有疫苗。在这里，我们报告了一种新的病毒 NS5 RNA 甲基转移酶抑制剂的发现，这是一个有前途的黄病毒药物靶点。我们使用多阶段分子对接方法，对超过 500 万个商业上可获得的化合物库进行了筛选，以针对该酶的两个结合位点。在选择进行实验验证的 263 种化合物中，我们发现了 10 种 IC50 值<100μM 的抑制剂，其中 4 种在体外试验中 IC50 值<10μM。初始命中列表还包含 25 种非特异性聚集剂。我们讨论了为什么这种情况可能发生在这个特定的靶点上。我们还描述了我们在发现这一点后，试图使用聚集预测进一步指导研究的尝试。
