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Discovery of potent HIV ‐1 non‐nucleoside reverse transcriptase inhibitors by exploring the structure–activity relationship of solvent‐exposed regions I
Author(s) -
Kang Dongwei,
Wang Zhao,
Chen Meng,
Feng Da,
Wu Gaochan,
Zhou Zhongxia,
Jing Lanlan,
Zuo Xiaofang,
Jiang Xiangyi,
Daelemans Dirk,
De Clercq Erik,
Pannecouque Christophe,
Zhan Peng,
Liu Xinyong
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13429
Subject(s) - reverse transcriptase , etravirine , linker , nevirapine , chemistry , docking (animal) , stereochemistry , mutant , pyrimidine , nucleoside , nucleotidyltransferase , enzyme , structure–activity relationship , human immunodeficiency virus (hiv) , biochemistry , virology , in vitro , biology , rna , gene , medicine , nursing , computer science , antiretroviral therapy , viral load , operating system
Two novel series of human immunodeficiency virus‐1 ( HIV ‐1) non‐nucleoside reverse transcriptase inhibitors ( NNRTI s) bearing a thiophene[3,2‐ d ]pyrimidine scaffold and sulfonamide linker in the right wing have been identified, which demonstrated activity against the wild‐type ( WT ) HIV ‐1 strain in MT ‐4 cells with inhibitory concentrations ranging from micromolar to submicromolar. Especially, against the mutant strains K103N and E138K, most compounds exhibited more potent activity than against WT HIV ‐1. Compound 7 ( EC 50 = 0.014, 0.031 μM) achieved the most potent activity against the two mutants, being more effective than that of nevirapine ( NVP , EC 50 = 7.572, 0.190 μM) and comparable to that of etravirine ( ETV , EC 50 = 0.004, 0.014 μM). Molecular docking experiments on the novel analogs have also suggested that the extensive network of main chain hydrogen bonds are important in the binding mode, which may provide valuable insights for further optimization.