2025/10/20 by Xiangkai Ji, Xiangyi Jiang, Heng Gao +6 · 1 citation
Biochemistry, Genetics and Molecular Biology · Chemistry · Medicine · #Chemical Synthesis and Analysis #Click Chemistry and Applications #Cocrystal #Drug discovery #Drug resistance #HIV/AIDS drug development and treatment #Hydrogen bond #Molecular model #Mutant #Reverse transcriptase
paper · doi:10.1021/acs.jmedchem.5c02211
published in Journal of Medicinal Chemistry 68(21), 23345-23362 (American Chemical Society)
openalex publication_date 2025/10/20 · openalex created_date 2025/10/21 · openalex updated_date 2026/08/01
Abstract There is an urgent need to develop next-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) to combat the rapid emergence of drug-resistant HIV-1 variants. Guided by cocrystal structures of ETR and K-5a2 bound to HIV-1 reverse transcriptase (RT), a privileged-fragment hybridization strategy was employed to enhance antiviral activity and resistance profiles. Through three rounds of optimization, compound 18d exhibited potent activity against wild-type (WT) and seven clinically relevant mutant HIV-1 strains, with EC50 values of 1.5–31 nM, surpassing ETR (2.6–41 nM). Molecular dynamics simulations revealed that the aminopyrimidine and pyridine fragments of 18d formed extensive hydrogen bonds with surrounding residues, contributing to its strong resistance barrier. Moreover, 18d displayed favorable metabolic stability in vivo (T1/2 = 1.42 h) and an excellent safety profile. Collectively, these findings highlight 18d as a promising next-generation NNRTI candidate for further development.