Structure-based virtual screening, synthesis and SAR of novel inhibitors of hepatitis C virus NS5B polymerase.
Structure-based virtual screening, synthesis and SAR of novel inhibitors of hepatitis C virus NS5B polymerase.
复制标题
DOI：
10.1016/j.bmc.2010.05.030
复制
发表时间：
2010-07-01
影响因子：
3.5
通讯作者：
Kaushik-Basu, Neerja
中科院分区：
文献类型：
--
作者：
Talele, Tanaji T.;Arora, Payal;Kulkarni, Shridhar S.;Patel, Maulik R.;Singh, Satyakam;Chudayeu, Maksim;Kaushik-Basu, Neerja
丙型肝炎病毒(丙型肝炎病毒)NS5B聚合酶是开发治疗丙型肝炎病毒感染的治疗药物的关键靶点。在这里，我们报道了通过基于结构的虚拟筛选、合成和构效关系(SAR)优化相结合的方法来鉴定新型丙型肝炎病毒NS5B变构抑制剂。针对NS5B的四环吲哚抑制剂结合口袋(变构口袋-1，AP-1)，从ChemBridge数据库中虚拟筛选260,000个化合物，依次将文库缩小4个数量级，产生23个候选化合物。对所选化合物的NS5B抑制活性进行了体外评价，结果命中率为17%，鉴定出两种新的化学类型。其中，化合物3，具有罗丹宁支架，被证明适合于生产性的合成孔径雷达勘探和合成修饰。结果，开发了25个IC50值在7.7到68.0μM之间的衍生品。对先导化合物28在NS5B的四环吲哚和亚苄基结合的变构口袋(分别为AP-1和AP-3)内的对接分析表明，这两个口袋之间存在拓扑相似之处。化合物28是一种新型的罗丹宁类似物，在低微摩尔水平范围内对NS5B具有抑制作用，有望成为未来开发更有效的NS5B抑制剂的先导。
Hepatitis C virus (HCV) NS5B polymerase is a key target for the development of therapeutic agents aimed at the treatment of HCV infections. Here we report on the identification of novel allosteric inhibitors of HCV NS5B through a combination of structure-based virtual screening, synthesis and structure-activity relationship (SAR) optimization approach. Virtual screening of 260,000 compounds from the ChemBridge database against the tetracyclic indole inhibitor binding pocket of NS5B (allosteric pocket-1, AP-1), sequentially down-sized the library by 4 orders of magnitude to yield 23 candidates. In vitro evaluation of the NS5B inhibitory activity of the in-silico selected compounds resulted in 17% hit rate, identifying two novel chemotypes. Of these, compound 3, bearing the rhodanine scaffold, proved amenable for productive SAR exploration and synthetic modification. As a result, 25 derivatives that exhibited IC50 values ranging from 7.7 to 68.0 μM were developed. Docking analysis of lead compound 28 within the tetracyclic indole- and benzylidene-binding allosteric pockets (AP-1 and AP-3, respectively) of NS5B revealed topological similarities between these two pockets. Compound 28, a novel rhodanine analog with NS5B inhibitory potency in the low micromolar level range may be a promising lead for future development of more potent NS5B inhibitors.
登录
查看更多内容
影响因子：
7.6
作者：
Betzi, Stephane;Eydoux, Cecilia;Canard, Bruno
通讯作者：
Canard, Bruno
影响因子：
5.4
作者：
Bressanelli, S;Tomei, L;De Francesco, R
通讯作者：
De Francesco, R
影响因子：
2.7
作者：
Chan, L;Pereira, O;Bédard, J
通讯作者：
Bédard, J
鉴定和表征香豆作为新型HCV NS5B聚合酶抑制剂。
影响因子：
14.9
作者：
Kaushik-Basu, Neerja;Bopda-Waffo, Alain;Talele, Tanaji T.;Basu, Amartya;Costa, Paulo R. R.;da Silva, Alcides J. M.;Sarafianos, Stefan G.;Noel, Francois
通讯作者：
Noel, Francois
影响因子：
25.7
作者：
Ferenci, P;Fried, MW;Reddy, KR
通讯作者：
Reddy, KR