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Updated: May 24, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Structure-based design of novel 2,4,5-trisubstituted pyrimidine derivatives as potent HIV-1 NNRTIs by exploiting the
Zhenzhen Zhou1, Minghui Xie1, Zongji Zhuo1
1Department 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.
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.
