Structure-activity relationship studies of indole-based compounds as small molecule HIV-1 fusion inhibitors targeting glycoprotein 41.
Structure-activity relationship studies of indole-based compounds as small molecule HIV-1 fusion inhibitors targeting glycoprotein 41.
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DOI：
10.1021/jm500344y
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发表时间：
2014-06-26
影响因子：
7.3
通讯作者：
Gochin M
中科院分区：
文献类型：
--
作者：
Zhou G;Sofiyev V;Kaur H;Snyder BA;Mankowski MK;Hogan PA;Ptak RG;Gochin M
我们先前描述了具有通过靶向跨膜糖蛋白gp 41的疏水口袋来抑制HIV-1融合的潜力的含吲哚化合物。在这里，我们报告的基本支架的优化和构效关系的研究，定义的形状，接触表面积和分子特性的作用。在结合、细胞-细胞融合和病毒复制测定中评价了30种新化合物。低于1 μM阈值，结合和生物活性之间的相关性减弱，表明细胞中活性的两亲性要求。最具活性的抑制剂6 j表现出0.6 μM的结合亲和力和0.2 μM的EC 50，抑制细胞-细胞融合和活病毒复制，并对T20耐药菌株具有活性。具有相同连接性的22个化合物在对接计算中显示出一致的姿态，其排序与生物活性相匹配。这项工作提供了对HIV-1融合的小分子抑制的需求的深入了解，并证明了一种有效的低分子量融合抑制剂。
We previously described indole-containing compounds with the potential to inhibit HIV-1 fusion by targeting the hydrophobic pocket of transmembrane glycoprotein gp41. Here we report optimization and structure–activity relationship studies on the basic scaffold, defining the role of shape, contact surface area, and molecular properties. Thirty new compounds were evaluated in binding, cell–cell fusion, and viral replication assays. Below a 1 μM threshold, correlation between binding and biological activity was diminished, indicating an amphipathic requirement for activity in cells. The most active inhibitor 6j exhibited 0.6 μM binding affinity and 0.2 μM EC50 against cell–cell fusion and live virus replication and was active against T20 resistant strains. Twenty-two compounds with the same connectivity displayed a consensus pose in docking calculations, with rank order matching the biological activity. The work provides insight into requirements for small molecule inhibition of HIV-1 fusion and demonstrates a potent low molecular weight fusion inhibitor.
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影响因子：
64.5
作者：
Eckert, DM;Malashkevich, VN;Kim, PS
通讯作者：
Kim, PS
铃木 - 米龙在酰化反应，范围和最新发展中的交叉偶联。
DOI：
10.3390/molecules18011188
发表时间：
2013-01-17
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Blangetti M;Rosso H;Prandi C;Deagostino A;Venturello P
通讯作者：
Venturello P
影响因子：
5.6
作者：
Hawkins, Paul C. D.;Nicholls, Anthony
通讯作者：
Nicholls, Anthony
影响因子：
2.9
作者：
Dimitrov, AS;Louis, JM;Blumenthal, R
通讯作者：
Blumenthal, R
影响因子：
3.5
作者：
He, Xiao-Yang;Lu, Lu;Xie, Lan
通讯作者：
Xie, Lan