化学
逆转录酶
人类免疫缺陷病毒(HIV)
对接(动物)
药代动力学
药品
核苷逆转录酶抑制剂
IC50型
抗药性
分子模型
立体化学
组合化学
药理学
生物化学
体外
病毒学
微生物学
护理部
核糖核酸
基因
生物
医学
作者
Yun Sun,Zhenzhen Zhou,Du Feng,Lanlan Jing,Fabao Zhao,Zhao Wang,Tao Zhang,Hao Lin,Hao Song,Erik De Clercq,Christophe Pannecouque,Peng Zhan,Xinyong Liu,Dongwei Kang
标识
DOI:10.1021/acs.jmedchem.2c00576
摘要
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent an indispensable part of anti-HIV-1 therapy. To discover novel HIV-1 NNRTIs with increased drug resistance profiles and improved pharmacokinetic (PK) properties, a series of novel diarylpyrimidine derivatives were generated via the cocrystal structure-based drug design strategy. Among them, 36a exhibited outstanding antiviral activity against HIV-1 IIIB and a panel of mutant strains (L100I, K103N, Y181C, Y188L, E138K, F227L + V106A, and RES056), with EC50 ranging from 2.22 to 53.3 nM. Besides, 36a was identified with higher binding affinity (KD = 2.50 μM) and inhibitory activity (IC50 = 0.03 μM) to HIV-1 RT. Molecular docking and molecular dynamics simulation were performed to rationalize the design and the improved drug resistance of these novel inhibitors. Additionally, 36a·HCl exhibited favorable PK (T1/2 = 5.12 h, F = 12.1%) and safety properties (LD50 > 2000 mg/kg). All these suggested that 36a·HCl may serve as a novel drug candidate anti-HIV-1 therapy.
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