进一步探索变构结合口袋的溶剂暴露耐受区域以发现新型HIV-1非核苷类逆转录酶抑制剂
Further Exploring Solvent-Exposed Tolerant Regions of Allosteric Binding Pocket for Novel HIV-1 NNRTIs Discovery.
作者信息
Kang Dongwei, Wang Zhao, Zhang Heng, Wu Gaochan, Zhao Tong, Zhou Zhongxia, Huo Zhipeng, Huang Boshi, Feng Da, Ding Xiao, Zhang Jian, Zuo Xiaofang, Jing Lanlan, Luo Wei, Guma Samuel, Daelemans Dirk, Clercq Erik De, Pannecouque Christophe, Zhan Peng, Liu Xinyong
机构信息
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, P. R. China.
Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium.
出版信息
ACS Med Chem Lett. 2018 Mar 1;9(4):370-375. doi: 10.1021/acsmedchemlett.8b00054. eCollection 2018 Apr 12.
Abstract
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 exhibited significant activity against the whole viral panel, being about 1.5-2.6-fold (WT, EC = 2.44 nM; L100I, EC = 4.24 nM; Y181C, EC = 4.80 nM; F227L + V106A, EC = 17.8 nM) and 4-5-fold (K103N, EC = 1.03 nM; Y188L, EC = 7.16 nM; E138K, EC = 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.
摘要
基于对二芳基嘧啶（DAPYs）与HIV-1逆转录酶（RT）结合模式的详细分析，我们设计了几个新型非核苷类逆转录酶抑制剂（NNRTIs）的子系列，旨在探索NNRTIs结合口袋（NNIBP）中溶剂暴露耐受区域的生物学相关化学空间。最有效的化合物对整个病毒组表现出显著活性，比参考药物依非韦伦（ETV）强效约1.5 - 2.6倍（野生型，EC = 2.44 nM；L100I，EC = 4.24 nM；Y181C，EC = 4.80 nM；F227L + V106A，EC = 17.8 nM）以及4 - 5倍（K103N，EC = 1.03 nM；Y188L，EC = 7.16 nM；E138K，EC = 3.95 nM）。此外，进行了分子模拟以了解这些新型NNRTIs的相互作用结合模式，并为下一步优化研究提供见解。
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3
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5
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7
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