In search of effective H1N1 neuraminidase inhibitor by molecular docking, antiviral evaluation and membrane interaction studies using NMR

Abstract

Considering the need for discovery of new antiviral drugs, in view to combat the issue of resistance particularly to anti-influenza drugs, a series of 2'-amino, 3'-amino and 2', 4'-dihydroxy chalcone derivatives were designed. Structure-based drug design was used to design inhibitors of influenza virus - H1N1 neuraminidase enzyme. These were further optimized by a combination of iterative medicinal chemistry principles and molecular docking. Based on the best docking scores, some chalcone derivatives were synthesized and characterized by infrared spectroscopy (IR) and proton nuclear magnetic resonance (NMR). The molecules were evaluated for their anti-influenza action against influenza A/Pune isolate/2009 (H1N1) virus by in vitro enzyme-based assay (neuraminidase inhibition assay). We have then selected few of them for multinuclear NMR studies, 31P NMR, in order to probe the molecular mechanism of their antiviral action. Reasonably good correlation between docking scores; anti-influenza activity; and 31P NMR results were observed. The computational predictions were in consensus with the experimental results. It was observed that among tested compounds, derivative 1A, viz. 2', 4'-dihydroxy-4-methoxy chalcone, showed highest activity (IC50 = 2.23 μmol/l) against the virus under study. This derivative 1A can be explored further to provide a future therapeutic option for the treatment and prophylaxis of H1N1 viral infections.

Isolation and Characterization of Two Chalcone Derivatives with Anti-Hepatitis B Virus Activity from the Endemic Socotraen Dracaena cinnabari (Dragon’s Blood Tree)

“…Their intriguing biological properties have been investigated as potential pharmacological compounds having the ability to target a wide range of human viruses, such as hepatitis B virus (HBV), hepatitis C virus, MERS-CoV, SARS-CoV, human rhinovirus, herpes simplex, HIV, and influenza virus. Many viral molecular targets have been demonstrated to be affected by chalcones, including reverse transcriptase, protease, neuraminidase, aminotransferases, peroxide dismutase, glutathione peroxidase, and other related enzymes [27][28][29][30].…”

A comprehensive review on the antiviral activities of chalcones

“…Figure 1 illustrates the main mechanisms of actions of chalcone derivatives that were reported in literature on different human viruses. Chalcones were shown to act on important viral molecular targets affecting different stages of viral replication cycle including; reverse transcriptase (RT) [31,32], IN [22,[33][34][35], protease [36][37][38], neuraminidase (NA) [39], aminotransferases [40], superoxide dismutase, glutathione peroxidase and other associated enzymes [40]. They were also found to act on important receptors such as CXCR4 chemokine receptors [41], US28 receptor of HCMV [27] and capsid pocket inside viral protein 1 (VP1) in rhinovirus [42].…”

“…NA became one of the major anti-viral targets of many natural and synthetic chalcones, as targeting it is crucial for the inhibition of the viral growth. 2 0 , 4 0 -dihydroxy-4-methoxy chalcone is derived from bioactive compounds in nature and presented a high activity in inhibiting H1N1 NA [39]. In a different study, H9N2, H1N1, novel H1N1 and oseltamivir-resistant novel H1N1 cells were targeted by natural products obtained from the acetone extract of Glycyrrhiza inflata including isoliquiritigenin (IC 50 (lg/mL) of 8.41 ± 0.39, 9.69 ± 0.37, 3.48 ± 0.19 and 3.42 ± 0.12, respectively) and echinantin (IC 50 (lg/ mL) of 5.80 ± 0.30, 5.70 ± 0.55, 2.49 ± 0.14 and 2.19 ± 0.06, respectively) [23].…”

Structure-aided drug development of potential neuraminidase inhibitors against pandemic H1N1 exploring alternate binding mechanism

“…The structures of the synthesized analogues were characterized by 1 H NMR and infrared spectroscopy (IR). Representative analogues were also characterized by 13 C NMR. NMR experiments were recorded on a 500, 700, 800 MHz Bruker Avance NMR and 600 MHz Varian NMR spectrometer in DMSO-d 6 solvent, and data were processed by using Bruker Topspin 2.1 software and Varian software.…”

“…Interestingly, there are several chalcones from plant sources which have been reported as H1N1-NA inhibitors [8][9][10][11], which do not have any structural resemblance with currently available drugs. Some chalcones have been designed, synthesized and tested against seasonal H1N1 neuraminidase enzyme in our previous work [12][13][14]. However, the anti-influenza activity exhibited by these chalcones is less.…”