2. Academic Validation
  3. Structure-Based Drug Design Yields Diarylpyrimidine Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Structure-Based Drug Design Yields Diarylpyrimidine Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

  • ACS Infect Dis. 2025 Sep 12;11(9):2607-2616. doi: 10.1021/acsinfecdis.5c00519.
Zhenzhen Zhou 1,  Jie Guo 1,  Xin Li 1,  Jinyuan Wu 1,  Erik De Clercq 2,  Christophe Pannecouque 2,  Peng Zhan 1 3,  Dongwei Kang 1 3,  Xinyong Liu 1 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, 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, 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.
  • 3 China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, P. R. China.
PMID: 40770940 DOI: 10.1021/acsinfecdis.5c00519
Abstract

Human immunodeficiency virus type-1 (HIV-1) resistance severely compromises the efficacy of non-nucleoside Reverse Transcriptase inhibitors (NNRTIs). This study developed novel DAPY-derived NNRTIs via a structure-based drug design strategy with K-5a2 as the lead. All designed compounds demonstrate potent Antiviral activity against the HIV-1 wild-type (WT) strain (EC50 = 3.03-21.1 nM). Notably, compound 19 was identified as the most potent inhibitor against a panel of clinically relevant mutant strains (EC50 = 5.03-37.7 nM) with resistance fold (RF) values (RF = 0.746-5.59) superior to that of ETR (RF = 1.11-15.5). Mechanistic studies confirmed that 19 potently inhibits HIV-1 RT (IC50 = 0.107 μM). Molecular docking and MM/GBSA calculations validate its stable binding with NNIBP, mediated by extensive hydrogen bond networks, hydrophobic interactions, and π-π stacking. Collectively, this work delivers 19 as a highly promising next-generation NNRTI lead compound with exceptional resilience against drug-resistant HIV-1.

Keywords

DAPYs; HIV-1; NNRTIs; drug resistance; fragment hybridization.

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