A study on catalytic and non-catalytic sites of H5N1 and H1N1 neuraminidase as the target for chalcone inhibitors

Abstract

The H1N1 pandemic in 2009 and the H5N1 outbreak in 2005 have shocked the world as millions of people were infected and hundreds of thousands died due to the infections by the influenza virus. Oseltamivir, the most common drug to block the viral life cycle by inhibiting neuraminidase (NA) enzyme, has been less effective in some resistant cases due to the virus mutation. Presently, the binding of 10 chalcone derivatives towards H5N1 and H1N1 NAs in the non-catalytic and catalytic sites was studied using molecular docking. The in silico study was also conducted for its drug-like likeness such as Lipinski Rule, mutagenicity, toxicity and pharmacokinetic profiles. The result demonstrates that two chalcones (1c and 2b) have the potential for future NA inhibitor development. Compound 1c inhibits H5N1 NA and H1N1 NA with IC50 of 27.63 µM and 28.11 µM, respectively, whereas compound 2b inhibits NAs with IC50 of 87.54 µM and 73.17 µM for H5N1 and H1N1, respectively. The in silico drug-like likeness prediction reveals that 1c is 62% better than 2b (58%) in meeting the criteria. The results suggested that 1c and 2b have potencies to be developed as non-competitive inhibitors of neuraminidase for the future development of anti-influenza drugs.

In Silico Targeting of influenza virus haemagglutinin receptor protein using Diosmetin, Tangeritin, and Anthocyanidins as potential drugs

“…Berberine, lycorine, hemanthamine, aloperin, and dendrobine act as antiinfluenza agents. Similarly, in silico docking studies of compounds as anti-influenza agents were reported in the literature (Hariyono et al, 2021;Mtambo and Kumalo 2022;Abdullahi et al, 2022a, b). Table 5 represented an overview of the current study and highlights top binding affinities and majorly interacting amino acid residues.…”

Computational study of nitro-benzylidene phenazine as dengue virus-2 NS2B-NS3 protease inhibitor

“…It should be noted, however, that 5 does not pass the criteria set for Pgp substrate as this compound potentially acts as a substrate for this protein. In addition, both compounds fail Caco2 permeability (<0.9) and PgpI and PgP II inhibitors criteria (Lin & Yamazaki, 2003;de Angelis and Turco, 2011;Hariyono et al, 2021).…”

“…The mutagenic and toxic potency of compounds were predicted by their AMES toxicity (No), hMTD (>0.477), hERG 1 and hERG 2 inhibitor (No), ORAT and LOAEL (>2000 mg/kg, hepatotoxicity (No), skin sensitisation (No), TP toxicity (>0.5) and Minnow toxicity (>-0.3) ( Huerta E, 2007 ; Barlow et al, 2009 ; Sorell, 2016 ; McCormick, 2017 ; Gadaleta et al, 2019 ; Hariyono et al, 2021 ). From the results presented in Table 5 , both hits are likely to be potentially toxic and mutagenic, raising an alarm that the further process would need structural optimisation.…”

Discovery of ligustrazine and chalcone derivatives as novel viral nucleoprotein nuclear export inhibitors against influenza viruses

“…It is important to note that B14 , B29 , B31 , and B32 possess chalcone structures. Such chemical entities had been previously reported to function as anti‐influenza agents through inhibiting neuraminidase 34 . Thus, we also evaluated the inhibitory activities of these four compounds on influenza virus neuraminidase.…”

“…Such chemical entities had been previously reported to function as anti-influenza agents through inhibiting neuraminidase. 34 Thus, we also evaluated the inhibitory activities of these four compounds on influenza virus neuraminidase. As shown in Table 4, these four compounds did not exhibit any neuraminidase inhibitory activity at the maximum test concentration (100 μM), while the neuraminidase inhibitor OSC played its role as expected with an IC 50 value of 40 nM.…”