Structure-based identification of small molecules against influenza A virus endonuclease: an in silico and in vitro approach

被引:2
|
作者
Disha, Sai K. [1 ]
Puranik, Rashmi [1 ]
Sudheesh, N. [1 ]
Kavitha, K. [1 ]
Fathima, Fajeelath [2 ]
Anu, K. R. [2 ]
Joseph, Alex [2 ]
Anitha, J. [1 ]
Arunkumar, G. [1 ]
Mudgal, Piya Paul [1 ]
机构
[1] Manipal Acad Higher Educ, Manipal Inst Virol, Manipal 576104, Karnataka, India
[2] Manipal Acad Higher Educ, Manipal Coll Pharmaceut Sci, Dept Pharmaceut Chem, Manipal 576104, Karnataka, India
来源
PATHOGENS AND DISEASE | 2020年 / 78卷 / 04期
关键词
influenza virus; polymerase acidic subunit; virtual screening; molecular docking; PHARMACOKINETIC PROPERTIES; BALOXAVIR MARBOXIL; ACCURATE DOCKING; DRUG DISCOVERY; GLIDE; INHIBITION; PROTEIN; MODEL;
D O I
10.1093/femspd/ftaa032
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Influenza viruses are known to cause acute respiratory illness, sometimes leading to high mortality rates. Though there are approved influenza antivirals available, their efficacy has reduced over time, due to the drug resistance crisis. There is a perpetual need for newer and better drugs. Drug screening based on the interaction dynamics with different viral target proteins has been a preferred approach in the antiviral drug discovery process. In this study, the FDA approved drug database was virtually screened with the help of Schrodinger software, to select small molecules exhibiting best interactions with the influenza A virus endonuclease protein. A detailed cytotoxicity profiling was carried out for the two selected compounds, cefepime and dolutegravir, followed by in vitro anti-influenza screening using plaque reduction assay. Cefepime showed no cytotoxicity up to 200 mu M, while dolutegravir was non-toxic up to 100 mu M in Madin-Darby canine kidney cells. The compounds did not show any reduction in viral plaque numbers indicating no anti-influenza activity. An inefficiency in the translation of the molecular interactions into antiviral activity does not necessarily mean that the molecules were inactive. Nevertheless, testing the molecules for endonuclease inhibition per se can be considered a worthwhile approach.
引用
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页数:10
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