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Ligand-based design, synthesis, computational insights, and in vitro studies of novel N-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease
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Ligand-based design, synthesis, computational insights, and in vitro studies of novel N-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease
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Ligand-based design, synthesis, computational insights, and in vitro studies of novel N-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease
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Journal Article
Ligand-based design, synthesis, computational insights, and in vitro studies of novel N-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease
2022
Overview
The global outbreak of the COVID-19 pandemic provokes scientists to make a prompt development of new effective therapeutic interventions for the battle against SARS-CoV-2. A new series of N-(5-nitrothiazol-2-yl)-carboxamido derivatives were designed and synthesised based on the structural optimisation principle of the SARS-CoV Mpro co-crystallized WR1 inhibitor. Notably, compound 3b achieved the most promising anti-SARS-CoV-2 activity with an IC
50
value of 174.7 µg/mL. On the other hand, compounds 3a, 3b, and 3c showed very promising SARS-CoV-2 Mpro inhibitory effects with IC
50
values of 4.67, 5.12, and 11.90 µg/mL, respectively. Compound 3b docking score was very promising (−6.94 kcal/mol) and its binding mode was nearly similar to that of WR1. Besides, the molecular dynamics (MD) simulations of compound 3b showed its great stability inside the binding pocket until around 40 ns. Finally, a very promising SAR was concluded to help to design more powerful SARS-CoV-2 Mpro inhibitors shortly.
HIGHLIGHTS
A new series of N-(5-nitrothiazol-2-yl)-carboxamido derivatives were designed and synthesised based on the structural optimisation principle.
In vitro antiviral activities against SARS-CoV-2 using SARS-CoV-2 cell-based inhibitory assay.
The anticipated inhibitory effects of the synthesised compounds (3a-g) towards the SARS-CoV-2 Mpro enzyme were emphasised by using the SARS-CoV-2 Mpro assay.
Molecular docking studies, molecular dynamics simulations for 100 ns, and MM-GBSA calculations were carried out for the newly synthesised compounds (3a-g) compared to the co-crystallized inhibitor (WR1).
ADMET and toxicity in silico studies were applied for the designed derivatives.
Finally, our interesting work rationale helped to conclude a very promising structure-activity relationship (SAR) finding.
Publisher
Taylor & Francis,Taylor & Francis Ltd,Taylor & Francis Group
Subject
/ COVID-19
/ Cysteine Endopeptidases - metabolism
/ Design
/ Enzymes
/ Humans
/ in vitro
/ Ligands
/ Molecular Docking Simulation
/ Molecular Dynamics Simulation
/ N-(5-nitrothiazol-2-yl)-carboxamido derivatives
/ Pharmacy
/ Protease Inhibitors - chemistry
/ Protease Inhibitors - pharmacology
/ Proteins
/ SAR
/ Severe acute respiratory syndrome coronavirus 2
/ Viral Nonstructural Proteins
/ Viruses
