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Updated: Aug 7, 2026
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Rational design of dual-site NNRTIs based on 2,4,5-trisubstituted pyrimidine scaffold for potent inhibition of
Xiangkai Ji1, Xiangyi Jiang1, Heng Gao1
1Department 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, Shandong University, 44 West Culture Road, Jinan, Shandong, 250012, China.
Abstract:
To overcome HIV-1 drug resistance, we developed a series of novel dual-site NNRTIs by introducing a rigid sp-hybridized alkyne linker, enabling simultaneous occupation of both the NNIBP and NNIAS of HIV-1 RT. Accordingly, 19 exhibited potent antiviral activity against the wild-type strain (EC50 = 4.9 nM) and retained strong activity against clinically relevant mutants, including K103 N (EC50 = 3.5 nM), E138K (EC50 = 7.8 nM), and the K103 N/Y181C double mutant (EC50 = 130 nM). Molecular dynamics simulations revealed stable occupancy of both binding sites, offering a structural basis for its potent antiviral activity. These findings highlight the potential of dual-site targeting for the development of next-generation HIV-1 NNRTIs.
