2. Academic Validation
  3. Further Exploring Solvent-Exposed Tolerant Regions of Allosteric Binding Pocket for Novel HIV-1 NNRTIs Discovery

Further Exploring Solvent-Exposed Tolerant Regions of Allosteric Binding Pocket for Novel HIV-1 NNRTIs Discovery

  • ACS Med Chem Lett. 2018 Mar 1;9(4):370-375. doi: 10.1021/acsmedchemlett.8b00054.
Dongwei Kang 1,  Zhao Wang 1,  Heng Zhang 1,  Gaochan Wu 1,  Tong Zhao 1,  Zhongxia Zhou 1,  Zhipeng Huo 1,  Boshi Huang 1,  Da Feng 1,  Xiao Ding 1,  Jian Zhang 1,  Xiaofang Zuo 1,  Lanlan Jing 1,  Wei Luo 1,  Samuel Guma 1,  Dirk Daelemans 2,  Erik De Clercq 2,  Christophe Pannecouque 2,  Peng Zhan 1,  Xinyong Liu 1
Affiliations

Affiliations

  • 1 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.
  • 2 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium.
PMID: 29670703 DOI: 10.1021/acsmedchemlett.8b00054
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 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.

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