标题:Further Exploring Solvent-Exposed Tolerant Regions of Allosteric Binding Pocket for Novel HIV-1 NNRTIs Discovery
作者:Kang, Dongwei; Wang, Zhao; Zhang, Heng; Wu, Gaochan; Zhao, Tong; Zhou, Zhongxia; Huo, Zhipeng; Huang, Boshi; Feng, Da; Ding, Xiao; 更多
作者机构:[Kang, Dongwei; Wang, Zhao; Zhang, Heng; Wu, Gaochan; Zhao, Tong; Zhou, Zhongxia; Huo, Zhipeng; Huang, Boshi; Feng, Da; Ding, Xiao; Zhang, Jian; Zuo, 更多
通讯作者:Zhan, P;Liu, XY
通讯作者地址:[Zhan, P; Liu, XY]Shandong Univ, Dept Med Chem, Key Lab Chem Biol, Minist Educ,Sch Pharmaceut Sci, 44 West Culture Rd, Jinan 250012, Shandong, Peoples 更多
来源:ACS MEDICINAL CHEMISTRY LETTERS
出版年:2018
卷:9
期:4
页码:370-375
DOI:10.1021/acsmedchemlett.8b00054
关键词:HIV-1; NNRTIs; DAPY; tolerant regions; drug design
摘要:Based on the detailed analysis of the binding mode of diarylpyrimidines (DAPYs) with HIV-1 RT, we designed several subseries of novel NNRTIs, with the aim to probe biologically relevant chemical space of solvent-exposed tolerant regions in NNRTIs binding pocket (NNIBP). The most potent compound 21a exhibited significant activity against the whole viral panel, being about 1.5-2.6-fold (WT, EC50 = 2.44 nM; L100I, EC50 = 4.24 nM; Y181C, EC50 = 4.80 nM; F227L + V106A, EC50 = 17.8 nM) and 4-5-fold (K103N, EC50 = 1.03 nM; Y188L, EC50 = 7.16 nM; E138K, EC50 = 3.95 nM) more potent than the reference drug ETV. Furthermore, molecular simulation was conducted to understand the binding mode of interactions of these novel NNRTIs and to provide insights for the next optimization studies.
收录类别:SCOPUS;SCIE
资源类型:期刊论文
原文链接:https://www.scopus.com/inward/record.uri?eid=2-s2.0-85045350440&doi=10.1021%2facsmedchemlett.8b00054&partnerID=40&md5=e28269627ebac9dfbc3a3431e643567d
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