2. Academic Validation
  3. Structure-based design of novel 2,4,5-trisubstituted pyrimidine derivatives as potent HIV-1 NNRTIs by exploiting the tolerant regions in NNTRIs binding pocket

Structure-based design of novel 2,4,5-trisubstituted pyrimidine derivatives as potent HIV-1 NNRTIs by exploiting the tolerant regions in NNTRIs binding pocket

  • Eur J Med Chem. 2025 Feb 27:289:117464. doi: 10.1016/j.ejmech.2025.117464.
Zhenzhen Zhou 1,  Minghui Xie 1,  Zongji Zhuo 1,  Yalin Wang 1,  Fabao Zhao 1,  Sining Tao 1,  Zhening Liang 1,  Erik De Clercq 2,  Christophe Pannecouque 2,  Peng Zhan 3,  Dongwei Kang 3,  Xinyong Liu 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR 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.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
  • 4 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 40048799 DOI: 10.1016/j.ejmech.2025.117464
Abstract

To promote the development of the new generation of HIV-1 non-nucleoside Reverse Transcriptase inhibitors (NNRTIs), a series of novel 2,4,5-trisubstituted pyrimidine derivatives targeting the "tolerant region I″ and "tolerant region II" of NNRTI binding pocket (NNIBP) were designed through multi-site binding strategy. Among them, 13a was demonstrated with an improved potency against wild-type (WT) and a panel of mutant HIV-1 strains with EC50 values ranging from 0.0062 to 0.25 μM, being superior to that of efavirenz (EFV, EC50 = 0.0080-0.37 μM). In addition, 13a was proved to have low cytotoxicity (CC50 = 160.7 μM) and high SI values (SI = 25254). Further HIV-1 RT inhibition assay demonstrated that 13a is a classical NNRTI with an IC50 value of 0.41 μM. Molecular docking and molecular dynamics simulations results illustrated its binding mode with HIV-1 RT. Overall, these enchanting results illuminated the potential of 13a as a promising lead for the development of the new generation HIV-1 NNRTIs drugs.

Keywords

2,4,5-Trisubstituted pyrimidine; DAPYs; Drug resistance; HIV-1; NNRTIs.

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