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Exploiting the tolerant region I of the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket. Part 2: Discovery of diarylpyrimidine derivatives as potent HIV-1 NNRTIs with high Fsp3 values and favorable drug-like properties
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2020-11-27 , DOI: 10.1016/j.ejmech.2020.113051
Xiangyi Jiang , Boshi Huang , Fisayo A. Olotu , Jing Li , Dongwei Kang , Zhao Wang , Erik De Clercq , Mahmoud E.S. Soliman , Christophe Pannecouque , Xinyong Liu , Peng Zhan

To yield potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with favorable drug-like properties, a series of novel diarylpyrimidine derivatives targeting the tolerant region I of the NNRTI binding pocket were designed, synthesized and biologically evaluated. The most active inhibitor 10c exhibited outstanding antiviral activity against most of the viral panel, being about 2-fold (wild-type, EC50 = 0.0021 μM), 1.7-fold (K103N, EC50 = 0.0019 μM), and slightly more potent (E138K, EC50 = 0.0075 μM) than the NNRTI drug etravirine (ETR). Additionally, 10c was endowed with relatively low cytotoxicity (CC50 = 18.52 μM). More importantly, 10c possessed improved drug-like properties compared to those of ETR with an increased Fsp3 (Fraction of sp3 carbon atoms) value. Furthermore, the molecular dynamics simulation and molecular docking studies were implemented to reveal the binding mode of 10c in the binding pocket. Taken together, 10c is a promising lead compound that is worth further investigation.



中文翻译:

利用非核苷类逆转录酶抑制剂(NNRTI)结合口袋的耐受区I。第2部分:发现具有高Fsp 3值和良好药物样特性的有效HIV-1 NNRTIs二芳基嘧啶衍生物

为了产生具有良好的药物样性质的有效的HIV-1非核苷逆转录酶抑制剂(NNRTIs),设计,合成和生物学评估了一系列靶向NNRTI结合口袋的I区的新型二芳基嘧啶衍生物。活性最高的抑制剂10c对大多数病毒板均表现出出色的抗病毒活性,约为2倍(野生型,EC 50 = 0.0021μM),1.7倍(K103N,EC 50 = 0.0019μM),并且效力更强(E138K,EC 50 = 0.0075μM )比NNRTI药物依曲韦林(ETR)高。此外,赋予10c较低的细胞毒性(CC 50 = 18.52μM)。更重要的是10c与ETR相比,Fsp 3具有改善的类药物特性,且Fsp 3(sp 3碳原子的分数)值增加。此外,进行了分子动力学模拟和分子对接研究以揭示10c在结合口袋中的结合模式。两者合计,10c是有前途的铅化合物,值得进一步研究。

更新日期:2020-11-27
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