2. Academic Validation
  3. Design, synthesis and evaluation of novel HIV-1 NNRTIs with dual structural conformations targeting the entrance channel of the NNRTI binding pocket

Design, synthesis and evaluation of novel HIV-1 NNRTIs with dual structural conformations targeting the entrance channel of the NNRTI binding pocket

  • Eur J Med Chem. 2016 Jun 10:115:53-62. doi: 10.1016/j.ejmech.2016.02.068.
Qing Meng 1,  Xuwang Chen 1,  Dongwei Kang 1,  Boshi Huang 1,  Wenxin Li 1,  Peng Zhan 1,  Dirk Daelemans 2,  Erik De Clercq 2,  Christophe Pannecouque 3,  Xinyong Liu 4
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, PR China.
  • 2 Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
  • 3 Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Electronic address: Christophe.Pannecouque@rega.kuleuven.be.
  • 4 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, PR China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 26994843 DOI: 10.1016/j.ejmech.2016.02.068
Abstract

On the basis of structure-based bioisosteric replacement and molecular hybridization strategy, a series of novel dual structural-conformation inhibitors targeting the "entrance channel" of HIV-1 NNRTIs binding pocket (NNIBP) were designed and synthesized. All of the new compounds were evaluated for their anti-HIV activities in MT-4 cells using the MTT method. Five compounds exhibited moderate to excellent potencies inhibiting wild-type (wt) HIV-1 replication with EC50 values ranging from 31.36 μM to 0.11 μM. Among them, compound 15b was identified as the most potent inhibitor with EC50 values of 0.11 μM and 2.18 μM against wt and K103N/Y181C double mutant HIV-1 strain (RES056), respectively. In addition, preliminary structure-activity relationships (SARs) and molecular simulation studies were discussed, which may provide valuable insights for further optimization.

Keywords

DAPY derivatives; Dual structural conformations; Entrance channel; HIV-1 NNRTIs; SARs.

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