Bioorganic chemistry · 2021
Design, synthesis, and antiviral evaluation of novel piperidine-substituted arylpyrimidines as HIV-1 NNRTIs by exploring the hydrophobic channel of NNIBP.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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Zhang Tao, Zhou Zhongxia, Zalloum Waleed A, Wang Zhao, Fu Zhipeng, Cherukupalli Srinivasulu, Feng Da, Sun Yanying, Gao Shenghua, De Clercq Erik, Pannecouque Christophe, Kang Dongwei, Zhan Peng, Liu Xinyong
Аннотация
Herein, alkenylpiperidine and alkynylpiperidine moieties were introduced into the left wing of DAPYs (diarylpyrimidines) to explore the new site of the NNIBP (non-nucleoside inhibitor binding pocket) protein-solvent interface region via the structure-based drug design strategy. All the synthesized compounds displayed nanomolar to submicromolar activity against WT (wild-type) HIV-1. Among all, compound FT1 (EC50 = 19 nM) was found to be the most active molecule, which is better than NVP (EC50 = 0.10 μM). In addition, most of the compounds displayed micromolar activity against K103N and E138K mutant strains, while FT1 (EC50(K103N) = 50 nM, EC50(E138K) = 0.19 µM) still has the most effective activity. The molecular dynamics simulation studies revealed that the presence of pyridine moiety of FT1 was essential and played a significant role in its binding with RT (reverse transcriptase).