Identification of novel potent HIV-1 inhibitors by exploiting the tolerant regions of the NNRTIs binding pocket.
Identification of novel potent HIV-1 inhibitors by exploiting the tolerant regions of the NNRTIs binding pocket.
复制标题
DOI：
10.1016/j.ejmech.2021.113204
复制
发表时间：
2021-01
影响因子：
6.7
通讯作者：
Yanying Sun;Dongwei Kang;Feng Da;Tao Zhang;Pei Li;Baodan Zhang;E. De Clercq;C. Pannecouque;P. Zhan;Xinyong Liu
中科院分区：
文献类型：
--
作者：
Yanying Sun;Dongwei Kang;Feng Da;Tao Zhang;Pei Li;Baodan Zhang;E. De Clercq;C. Pannecouque;P. Zhan;Xinyong Liu
以我们以前发现的NNRTIs 25 a和HBS-11 cas为先导，通过分子杂交策略设计了一系列新型噻吩并[3，2-d]嘧啶和噻吩并[2，3-d]嘧啶衍生物。对所有目标化合物进行了抗HIV-1活性和MT-4细胞毒性的评价。化合物16 a1和16 b1是对WT和突变型HIV-1毒株（L100 I、K103 N和E138 K）最有效的抑制剂，EC 50值范围为0.007 μM至0.043 μM。令人满意的是，与铅25 a（在pH 7.0时S < 1 μg/mL，CC 50 = 2.30 μM）相比，16 b1表现出显著降低的细胞毒性（CC 50> 217.5 μM）和改善的水溶性（在pH 7.0时S = 49.3 μg/mL）。此外，还进行了分子对接，以合理化这些新的衍生物的结构-活性关系，并了解它们与结合口袋的关键相互作用。
With our previously identified potent NNRTIs25aandHBS-11cas leads, series of novel thiophene[3,2-d]pyrimidine and thiophene[2,3-d]pyrimidine derivatives were designedviamolecular hybridization strategy. All the target compounds were evaluated for their anti-HIV-1 activity and cytotoxicity in MT-4 cells. Compounds16a1and16b1turned out to be the most potent inhibitors against WT and mutant HIV-1 strains (L100I, K103N, and E138K), with EC50values ranging from 0.007 μM to 0.043 μM. Gratifyingly,16b1exhibited significantly reduced cytotoxicity (CC50> 217.5 μM) and improved water solubility (S = 49.3 μg/mL at pH 7.0) compared to the lead 25a (S < 1 μg/mL at pH 7.0, CC50= 2.30 μM). Moreover, molecular docking was also conducted to rationalize the structure-activity relationships of these novel derivatives and to understand their key interactions with the binding pocket.