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Towards discovering dual functional inhibitors against both wild type and K103N mutant HIV-1 reverse transcriptases: molecular docking and QSAR studies on 4,1-benzoxazepinone analogues

文献类型：期刊论文

作者Zhang, Zhenshan; Zheng, Mingyue; Du, Li; Shen, Jianhua; Luo, Xiaomin; Zhu, Weiliang; Jiang, Hualiang
刊名JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
出版日期2006-05
卷号20期号:5页码:281-293
关键词HIV-1 reverse transcriptase 3D-QSAR 4,1-benzoxazepinones K103N mutant
ISSN号0920-654X
DOI10.1007/s10822-006-9050-6
文献子类Article
英文摘要To find useful information for discovering dual functional inhibitors against both wild type (WT) and K103N mutant reverse transcriptases (RTs) of HIV-1, molecular docking and 3D-QSAR approaches were applied to a set of twenty-five 4,1-benzoxazepinone analogues of efavirenz (SUSTIVA (R)), some of them are active against the two RTs. 3D-QSAR models were constructed, based on their binding conformations determined by molecular docking, with r(cv)(2) values ranging from 0.656 to 0.834 for CoMFA and CoMSIA, respectively. The models were then validated to be highly predictive and extrapolative by inhibitors in two test sets with different molecular skeletons. Furthermore, CoMFA models were found to be well matched with the binding sites of both WT and K103N RTs. Finally, a reasonable pharmacophore model of 4,1-benzoxazepinones were established. The application of the model not only successfully differentiated the experimentally determined inhibitors from non-inhibitors, but also discovered two potent inhibitors from the compound database SPECS. On the basis of both the 3D-QSAR and pharmacophore models, new clues for discovering and designing potent dual functional drug leads against HIV-1 were proposed: (i) adopting positively charged aliphatic group at the cis-substituent of C3; (ii) reducing the electronic density at the position of O4; (iii) positioning a small branched aliphatic group at position of C5; (iv) using the negatively charged bulky substituents at position of C7.
WOS关键词HUMAN-IMMUNODEFICIENCY-VIRUS ; ORBITAL ELECTRONEGATIVITY ; NONNUCLEOSIDE INHIBITOR ; ANTIRETROVIRAL THERAPY ; EFAVIRENZ DMP-266 ; STRUCTURAL BASIS ; DRUG-RESISTANCE ; FIELD ANALYSIS ; MUTATIONS ; DERIVATIVES
WOS研究方向Biochemistry & Molecular Biology ; Biophysics ; Computer Science
语种英语
WOS记录号WOS:000241554400002
出版者SPRINGER
源URL[http://119.78.100.183/handle/2S10ELR8/273610]  
专题药物发现与设计中心
通讯作者Zhu, Weiliang
作者单位1.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, Ctr Drug Discovery & Design,State Key Lab Drug Re, Shanghai 201203, Peoples R China
2.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Zhenshan,Zheng, Mingyue,Du, Li,et al. Towards discovering dual functional inhibitors against both wild type and K103N mutant HIV-1 reverse transcriptases: molecular docking and QSAR studies on 4,1-benzoxazepinone analogues[J]. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,2006,20(5):281-293.
APA Zhang, Zhenshan.,Zheng, Mingyue.,Du, Li.,Shen, Jianhua.,Luo, Xiaomin.,...&Jiang, Hualiang.(2006).Towards discovering dual functional inhibitors against both wild type and K103N mutant HIV-1 reverse transcriptases: molecular docking and QSAR studies on 4,1-benzoxazepinone analogues.JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,20(5),281-293.
MLA Zhang, Zhenshan,et al."Towards discovering dual functional inhibitors against both wild type and K103N mutant HIV-1 reverse transcriptases: molecular docking and QSAR studies on 4,1-benzoxazepinone analogues".JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 20.5(2006):281-293.

入库方式： OAI收割

来源：上海药物研究所

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