Thiazolidinones: Potential Human Novel Coronavirus (SARS-CoV-2) Protease Inhibitors Against COVID-19
2020
COVID-19 is a rapidly
spreading infectious disease caused by a novel beta coronavirus
SARS-CoV-2. During the 1980's coronavirus, genomic RNA was transcribed into a
set of subgenomic mRNAs that encode viral proteins containing a leader sequence
derived from the 5' end of the genome. The subgenomic mRNAs are transcribed
from negative-strand RNAs, synthesized for the full-length genomic RNA - a
unique mechanism, presumed to occur by a process involving viral polymerase
jumping from one part of the genome template to another, leading to high rate
of recombination for coronaviruses, playing role in viral interspecies
infections. The sequence of SARS-CoV-2 confined that spike protein has furin
cleavage site in the S1/S2 junction different from SARS-CoV and other closely
related viruses. This has proved the possibility of Protease inhibitors as
antivirals has led to the speculation about virulence and pathogenesis, and it
is also possible that this new furin site may serve as a marker to identify a
possible precursor virus. This novel
human coronavirus (SARS-CoV-2) has resulted in a large number of fatalities and
incapacitated human health system. No treatment is available, and a vaccine
will not be available for several months. Hence, the protease of coronavirus is
a promising target for antiviral drug discovery.
We herein report a new generation of thiazolidinone
derivatives, inhibitors of SARS-CoV-2 coronavirus protease that incorporated
thiazolidinone heterocycles as N-terminal capping groups of the peptide
moiety. The compounds were extensively characterized with respect to
inhibition of various proteases, inhibition mechanism, membrane permeability,
antiviral activity. Our research group has recently designed a one-pot
three-component reaction and its mechanism was studied through DFT. Further, a
library of the molecules based on the products is designed. These novel
molecules were screened through ADMET and molecular docking to find out the
potential inhibitor of SARS-CoV-2 protease, as they may have competitive
inhibition mechanisms, in correlation with their membrane permeability, a more
pronounced antiviral activity.
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