Development of a NS2B/NS3 protease inhibition assay using AlphaScreen® beads for screening of anti-dengue activities

Abduraman, Muhammad Asyraf; Hariono, Maywan; Yusof, Rohana; Rahman, Noorsaadah Abd.; Wahab, Habibah A.; Tan, Mei Lan

doi:10.1016/j.heliyon.2018.e01023

Cited by 12 publications

(8 citation statements)

References 60 publications

(97 reference statements)

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“…Fortunately, homology modelling has been performed to solve this problem by utilising the DENV2 apo-enzyme structure with the ligand from West Nile Virus (WNV) NS2B-NS3 protease crystal structure ( Wichapong et al, 2010 ). This model was successfully used in finding hits to lead in a few projects of DENV2 NS2B-NS3 protease inhibitor discovery bearing thioguanine ( Abduraman et al, 2018 ; Hariono et al, 2019 ), benzofuranone ( Sulaiman et al, 2019 ), and malabaricone-acylphenol ( Sivasothy et al, 2021 ). Consequently, the homology model of DENV2 NS2B-NS3 protease structure was chosen in designing the corresponding target inhibitor from the nitro-benzylidene phenazine compound.…”

Section: Discussionmentioning

confidence: 99%

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

Salin

Hariono

Khalili

et al. 2022

Front. Mol. Biosci.

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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.

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Section: Discussionmentioning

confidence: 99%

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

Salin

Hariono

Khalili

et al. 2022

Front. Mol. Biosci.

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“…When the product was formed, the mixture was then washed with Na 2 CO 3 10%, followed by filtration. The solid product was collected and recrystallized using suitable organic solvents (adapted from refs − ). The characterization and the NMR spectra of the compounds are presented in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

Arylamide as Potential Selective Inhibitor for Matrix Metalloproteinase 9 (MMP9): Design, Synthesis, Biological Evaluation, and Molecular Modeling

Hariono

Nuwarda

Yusuf

et al. 2019

J. Chem. Inf. Model.

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Previous studies have reported that compounds bearing an arylamide linked to a heterocyclic planar ring have successfully inhibited the hemopexin-like domain (PEX9) of matrix metalloproteinase 9 (MMP9). PEX9 has been suggested to be more selectively targeted than MMP9’s catalytic domain in a degrading extracellular matrix under some pathologic conditions, especially in cancer. In this study, we aim to synthesize and evaluate 10 arylamide compounds as MMP9 inhibitors through an enzymatic assay as well as a cellular assay. The mechanism of inhibition for the most active compounds was investigated via molecular dynamics simulation (MD). Molecular docking was performed using AutoDock4.0 with PEX9 as the protein model to predict the binding of the designed compounds. The synthesis was carried out by reacting aniline derivatives with 3-bromopropanoyl chloride using pyridine as the catalyst at room temperature. The MMP9 assay was conducted using the FRET-based MMP9 kits protocol and gelatin zymography assay. The cytotoxicity assay was done using the MTT method, and the MD simulation was performed using AMBER16. Assay on MMP9 demonstrated activities of three compounds (2, 7, and 9) with more than 50% inhibition. Further inhibition on MMP9 expressed by 4T1 showed that two compounds (7 and 9) inhibited its gelatinolytic activity more than 50%. The cytotoxicity assay against 4T1 cells results in the inhibition of the cell growth with an EC50 of 125 μM and 132 μM for 7 and 9, respectively. The MD simulation explained a stable interaction of 7 and 9 in PEX9 at 100 ns with a free energy of binding of −8.03 kcal/mol and −6.41 kcal/mol, respectively. Arylamides have potential effects as selective MMP9 inhibitors in inhibiting breast cancer cell progression.

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“…The authors have cited additional references within the Supporting Information [27,41,47,52–54,56,64–89] …”

Section: Supporting Informationmentioning

confidence: 99%

Next Generation of Fluorometric Protease Assays: 7‐Nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl‐amides (NBD‐Amides) as Class‐Spanning Protease Substrates

Maus

Müller

Development of a NS2B/NS3 protease inhibition assay using AlphaScreen® beads for screening of anti-dengue activities

Cited by 12 publications

References 60 publications

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

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

Arylamide as Potential Selective Inhibitor for Matrix Metalloproteinase 9 (MMP9): Design, Synthesis, Biological Evaluation, and Molecular Modeling

Next Generation of Fluorometric Protease Assays: 7‐Nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl‐amides (NBD‐Amides) as Class‐Spanning Protease Substrates

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