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@ARTICLE{Olubiyi:877948,
author = {Olubiyi, Olujide and Olagunju, Maryam and Keutmann, Monika
and Loschwitz, Jennifer and Strodel, Birgit},
title = {{H}igh {T}hroughput {V}irtual {S}creening to {D}iscover
{I}nhibitors of the {M}ain {P}rotease of the {C}oronavirus
{SARS}-{C}o{V}-2},
journal = {Molecules},
volume = {25},
number = {14},
issn = {1420-3049},
address = {Basel},
publisher = {MDPI},
reportid = {FZJ-2020-02527},
pages = {3193 -},
year = {2020},
abstract = {We use state-of-the-art computer-aided drug design (CADD)
techniques to identify prospective inhibitors of the main
protease enzyme, 3CLpro of the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. From
our screening of over one million compounds including
approved drugs, investigational drugs, natural products, and
organic compounds, and a rescreening protocol incorporating
enzyme dynamics via ensemble docking, we have been able to
identify a range of prospective 3CLpro inhibitors.
Importantly, some of the identified compounds had previously
been reported to exhibit inhibitory activities against the
3CLpro enzyme of the closely related SARS-CoV virus. The
top-ranking compounds are characterized by the presence of
multiple bi- and monocyclic rings, many of them being
heterocycles and aromatic, which are flexibly linked
allowing the ligands to adapt to the geometry of the 3CLpro
substrate site and involve a high amount of functional
groups enabling hydrogen bond formation with surrounding
amino acid residues, including the catalytic dyad residues
H41 and C145. Among the top binding compounds we identified
several tyrosine kinase inhibitors, which include a
bioflavonoid, the group of natural products that binds best
to 3CLpro. Another class of compounds that decently binds to
the SARS-CoV-2 main protease are steroid hormones, which
thus may be endogenous inhibitors and might provide an
explanation for the age-dependent severity of COVID-19. Many
of the compounds identified by our work show a considerably
stronger binding than found for reference compounds with in
vitro demonstrated 3CLpro inhibition and anticoronavirus
activity. The compounds determined in this work thus
represent a good starting point for the design of inhibitors
of SARS-CoV-2 replication.},
cin = {IBI-7},
ddc = {540},
cid = {I:(DE-Juel1)IBI-7-20200312},
pnm = {551 - Functional Macromolecules and Complexes (POF3-551)},
pid = {G:(DE-HGF)POF3-551},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:32668701},
UT = {WOS:000557286200001},
doi = {10.3390/molecules25143193},
url = {https://juser.fz-juelich.de/record/877948},
}