吗啉
化学
HIV-1蛋白酶
配体(生物化学)
立体化学
效力
蛋白酶
生物信息学
IC50型
蛋白酶抑制剂(药理学)
EC50型
体内
细胞毒性
酶
胺气处理
铅化合物
体外
生物化学
人类免疫缺陷病毒(HIV)
有机化学
病毒学
受体
生物技术
生物
基因
抗逆转录病毒疗法
病毒载量
作者
Mei Zhu,Huiyu Zhou,Ling Ma,Biao Dong,Jiwei Ding,Jinming Zhou,Juxian Wang,Guoning Zhang,Minghua Wang,Qi Shan,Shan Cen,Mei Zhu
标识
DOI:10.1016/j.ejmech.2022.114251
摘要
By following up on the design vector of optimizing amine-based HIV-1 protease inhibitors, we have designed and biologically evaluated a novel class of inhibitors with the free nitrogen or sulphone in morpholine cores as P2 ligands in combination with diverse substituted phenylsulfonamide P2' ligands. As it turns out, a majority of these inhibitors exhibit prominent enzymatic inhibitory activity in low nanomolar ranges with relatively low cytotoxicity. Particularly, inhibitor 1e containing a morpholine carboxamide P2 ligand and a 4-hydroxyphenylsulfonamide P2' ligand illustrates a robust enzyme inhibitory IC50 value of 90 pM. Furthermore, 1e demonstrates impressive in vivo antiviral activity with EC50 value of 89 nM and a degree of inhibitory potency against the DRV-resistant variant. More importantly, 1e exhibits remarkable activity with EC50 values of 13.59 nM and 8.23 nM against subtype C HIV-1 strains ZM246 and Indie, respectively. Furthermore, the in silico studies provide molecular insights into binding features of inhibitors with HIV-1 protease, and furnish a valuable forecast on further process.
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