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Heterocyclic pharmacochemistry of new rhinovirus antiviral agents: A combined computational and experimental study
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2017-09-21 , DOI: 10.1016/j.ejmech.2017.09.036
Laurène Da Costa , Els Scheers , Antonio Coluccia , Alessia Rosetti , Manon Roche , Johan Neyts , Thierry Terme , Roberto Cirilli , Carmen Mirabelli , Romano Silvestri , Patrice Vanelle

Rhinovirus (RV), member of the Enterovirus genus, is known to be involved in more than half of the common colds. Through advances in molecular biology, rhinoviruses have also been associated with exacerbations of chronic pulmonary diseases (e.g. asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis). In the current investigation, we develop a novel series of 4,5-dimethoxybenzyl derivatives that potently inhibits rhinovirus replication. Compound (S)-7f blocks RV-B14 replication with an EC50 value of 0.25 μM and shows a low toxicity in HeLa cells (CC50 > 271 μM). Enantioseparation followed by an absolute configuration determination by a Mosher's method revealed the interest of enantiopure compounds. Molecular docking studies permitted the identification of key biological interactions within the drug-binding pocket and an in silico drug-like study revealed a good potential for the development of these derivatives.



中文翻译:

新型鼻病毒抗病毒药的杂环药理学:计算和实验相结合的研究

鼻病毒(RV)是肠道病毒属的成员,已知参与了一半以上的普通感冒。通过分子生物学的进步,鼻病毒还与慢性肺部疾病(例如哮喘,慢性阻塞性肺部疾病(COPD)和囊性纤维化)的恶化相关。在当前的调查中,我们开发了一种新型的4,5-二甲氧基苄基衍生物,可有效抑制鼻病毒复制。化合物(S) -7f阻断RV-B14复制,EC 50值为0.25μM,并且在HeLa细胞中显示低毒性(CC 50 > 271μM)。进行对映体分离,然后通过Mosher方法进行绝对构型测定,揭示了对映体纯化合物的重要性。分子对接研究允许在药物结合口袋中鉴定关键的生物相互作用,计算机模拟药物研究显示了开发这些衍生物的良好潜力。

更新日期:2017-09-21
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