Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays

Boshi Huang; Xueshun Wang; Xinhao LiuZihui ChenWanzhuo LiSongkai SunHuiqing LiuDirk DaelemansErik De ClercqChristophe PannecouquePeng ZhanXinyong Liu

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Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays

机译：Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays

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Graphical abstract A novel series of DAPY-IAS hybrid derivatives were identified as newer HIV-1 NNRTIs using structure-based molecular hybridization. Display Omitted Abstract Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC 50 values of 1.48 μM and 1.61 μM, respectively. They were much potent than the reference drug ddI (EC 50 = 76.0 μM) and comparable to 3TC (EC 50 = 2.54 μM). Compound 7a also exhibited the favorable selectivity index (SI = 80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed. ]]>

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《Bioorganic and medicinal chemistry》 |2017年第16期|4397-4406|共10页
作者
Boshi Huang; Xueshun Wang; Xinhao LiuZihui ChenWanzhuo LiSongkai SunHuiqing LiuDirk DaelemansErik De ClercqChristophe PannecouquePeng ZhanXinyong Liu;
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作者单位

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education),;

Rega Institute for Medical Research, KU Leuven;

Department of Pharmacology, School of Medicine, Shandong University;

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正文语种英语
中图分类药学;
关键词
HIV-1 inhibitors; DAPY-IAS hybrids; Crystallographic overlays; Drug design; SARs; Molecular modeling;

Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays

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