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Docking study of flavonoid derivatives as potent inhibitors of influenza H1N1 virus neuraminidase.

ABSTRACT: Influenza type A is considered as a severe public health concern. The mechanism of drugs applied for the control of this virus depends on two surface glycoproteins with antigenic properties, namely hemagglutinin (HA) and neuraminidase (NA). HA aids the virus to penetrate cells in the early stage of infection and NA is an enzyme with the ability to break glycoside bonds, which enables virion spread through the host cell membrane. Since NA contains a relatively preserved active site, it has been an important target in drug design. Oseltamivir is a common drug used for the treatment of influenza infections, for which cases of resistance have recently been reported, giving rise to health concerns. Flavonoids are natural polyphenolic compounds with potential blocking effects in the neuraminidase active site. Based on their antiviral effect, the flavonoids quercetin, catechin, naringenin, luteolin, hispidulin, vitexin, chrysin and kaempferol were selected in the present study and compared alongside oseltamivir on molecular docking, binding energy and active site structure, in order to provide insight on the potential of these compounds as targeted drugs for the control and treatment of influenza type A. The molecular characterization of flavonoids with binding affinity was performed using AutoDock Vina software. The results indicated that these compounds may effectively block the NA active site. Therefore, these natural compounds derived from fruits have the potential for development into drugs for controlling influenza, which may aid overcome the clinical challenge of the H1N1 strain epidemic.

SUBMITTER: Sadati SM

PROVIDER: S-EPMC6299203 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundInfluenza virus disease remains one of the most contagious diseases that aided the deaths of many patients, especially in this COVID-19 pandemic era. Recent discoveries have shown that the high prevalence of influenza and SARS-CoV-2 coinfection can rapidly increase the death rate of patients. Hence, it became necessary to search for more potent inhibitors for influenza disease therapy. The present study utilized some computational modeling concepts such as 2D-QSAR, 3D-QSAR, molecular docking simulation, and ADMET predictions of some 1,3-thiazine derivatives as inhibitors of influenza neuraminidase (NA).ResultsThe 2D-QSAR modeling results showed GFA-MLR ( Rtrain2 = 0.9192, Q 2 = 0.8767, R 2 adj = 0.8991, RMSE = 0.0959, Rtest2 = 0.8943, Rpred2 = 0.7745) and GFA-ANN ( Rtrain2 = 0.9227, Q 2 = 0.9212, RMSE = 0.0940, Rtest2 = 0.8831, Rpred2 = 0.7763) models with the computed descriptors as ATS7s, SpMax5_Bhv, nHBint6, and TDB9m for predicting the NA inhibitory activities of compounds which have passed the global criteria of accepting QSAR model. The 3D-QSAR modeling was carried out based on the comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA). The CoMFA_ES ( Rtrain2 = 0.9620, Q 2 = 0.643) and CoMSIA_SED ( Rtrain2 = 0.8770, Q 2 = 0.702) models were found to also have good and reliable predicting ability. The compounds were also virtually screened based on their binding scores via molecular docking simulations with the active site of the NA (H1N1) target receptor which also confirms their resilient potency. Four potential lead compounds (4, 7, 14, and 15) with the relatively high inhibitory rate (> 50%) and docking (> - 6.3 kcal/mol) scores were identified as the possible lead candidates for in silico exploration of improved anti-influenza agents.ConclusionThe drug-likeness and ADMET predictions of the lead compounds revealed non-violation of Lipinski's rule and good pharmacokinetic profiles as important guidelines for rational drug design. Hence, the outcome of this research set a course for the in silico design and exploration of novel NA inhibitors with improved potency.

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Docking study of flavonoid derivatives as potent inhibitors of influenza H1N1 virus neuraminidase.

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