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

Abstract

According to the World Health Organisation (WHO), as of week 23 of 2022, there were more than 1,311 cases of dengue in Malaysia, with 13 deaths reported. Furthermore, there was an increase of 65.7% during the same period in 2021. Despite the increase in cumulative dengue incidence, there is no effective antiviral drug available for dengue treatment. This work aimed to evaluate several nitro-benzylidene phenazine compounds, especially those that contain 4-hydroxy-3,5-bis((2-(4-nitrophenyl)hydrazinylidene)-methyl)benzoate through pharmacophore queries selection method as potential dengue virus 2 (DENV2) NS2B-NS3 protease inhibitors. Herein, molecular docking was employed to correlate the energies of selected hits’ free binding and their binding affinities. Pan assay interference compounds (PAINS) filter was also adopted to identify and assess the drug-likeness, toxicity, mutagenicity potentials, and pharmacokinetic profiles to select hit compounds that can be considered as lead DENV2 NS2B-NS3 protease inhibitors. Molecular dynamics assessment of two nitro-benzylidene phenazine derivatives bearing dinitro and hydroxy groups at the benzylidene ring showed their stability at the main binding pocket of DENV2 protease, where their MM-PBSA binding energies were between -22.53 and -17.01 kcal/mol. This work reports those two nitro-benzylidene phenazine derivatives as hits with 52–55% efficiency as antiviral candidates. Therefore, further optimisation is required to minimise the lead compounds’ toxicity and mutagenicity.

The brief overview, antivirus and anti-SARS-CoV-2 activity, quantitative methods, and pharmacokinetics of cepharanthine: a potential small-molecule drug against COVID-19

“…It is important to consider whether CEP is a pan-assay interference compound (PAINS), given its bioactivity in so many in vitro and in vivo models. In recent years, the PAINS hypothesis has been widely used in the early screening of new drugs ( Baell and Holloway, 2010 ; Pouliot and Jeanmart, 2016 ; Nelson et al, 2017 ; Adnan et al, 2022 ; Salin et al, 2022 ; Das et al, 2023 ). For example, curcumin has been classified as a typical PAINS compound due to its invalid metabolic panacea properties as its clinical studies have not provided strong evidence for a therapeutic effect ( Nelson et al, 2017 ).…”

“…They designed, constructed, and fully disclosed a database for a PAINS filter (PAINS-Remover, http://cbligand.org/PAINS/ ) to remove PAINS from screening libraries and exclude them from bioassays ( Baell and Holloway, 2010 ). This PAINS filter has been widely recognized in the industry ( Baell and Holloway, 2010 ; Pouliot and Jeanmart, 2016 ; Adnan et al, 2022 ; Salin et al, 2022 ; Das et al, 2023 ). We have screened the possibility of CEP being a PAINS compound.…”

Synthesis and biological activity of imidazole phenazine derivatives as potential inhibitors for NS2B-NS3 dengue protease

“…The only comparative research was observed in silico , where two nitro-benzylidene phenazine derivatives ( Fig. 1 A and B ) with pharmacophore hit of 52 %–55 %, demonstrated their stability in the primary binding pocket of NS2B-NS3 protease with MM-PBSA binding energies ranging from −22.53 to −17.01 kcal mol −1 , indicating probable binding in DENV2 NS2B-NS3 protease [ 21 ].

Fig.

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“…1 Reported phenazine and imidazole motifs as anti-dengue inhibitors. (A) and (B) The nitro-benzylidene phenazine derivatives reported as potential inhibitors of DENV2 NS2B-NS3 ( in silico study) [ 21 ]. (C) Imidazole nucleoside derivatives reported as DENV2 NS2B-NS3 inhibitor [ 25 ].…”