bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Ноя. 15, 2023
Abstract
To
identify
starting
points
for
therapeutics
targeting
SARS-CoV-2,
the
Paul
Scherrer
Institute
and
Idorsia
decided
to
collaboratively
perform
an
X-ray
crystallographic
fragment
screen
against
its
main
protease.
Fragment-based
screening
was
carried
out
using
crystals
with
a
pronounced
open
conformation
of
substrate
binding
pocket.
Of
631
fragments
soaked,
total
29
hits
bound
either
in
active
site
(24
hits),
remote
pocket
(2
hits)
or
at
crystal
packing
interfaces
(3
hits).
Notably,
two
pose
sterically
incompatible
more
occluded
form
were
identified.
Two
isatin-based
electrophilic
covalently
catalytic
cysteine
residue.
Our
structures
also
revealed
surprisingly
strong
influence
on
three
published
used
as
positive
controls,
implications
by
crystallography.
Synopsis
An
SARS-CoV-2
3CL
protease
resulted
hits,
including
reversible
covalent
binders,
soaking
additional
reference
fragments.
Molecules,
Год журнала:
2024,
Номер
29(13), С. 3186 - 3186
Опубликована: Июль 4, 2024
Cancer
remains
a
leading
cause
of
death
worldwide,
often
resulting
from
uncontrolled
growth
in
various
organs.
Protein
kinase
inhibitors
represent
an
important
class
targeted
cancer
therapies.
Recently,
the
kinases
BRAF
and
VEGFR-2
have
shown
synergistic
effects
on
tumor
progression.
Seeking
to
develop
dual
BRAF/VEGFR-2
inhibitors,
we
synthesized
18
amino-benzothiazole
derivatives
with
structural
similarities
reported
inhibitors.
Four
compounds-
Acta Crystallographica Section D Structural Biology,
Год журнала:
2024,
Номер
80(2), С. 123 - 136
Опубликована: Янв. 30, 2024
To
identify
starting
points
for
therapeutics
targeting
SARS-CoV-2,
the
Paul
Scherrer
Institute
and
Idorsia
decided
to
collaboratively
perform
an
X-ray
crystallographic
fragment
screen
against
its
main
protease.
Fragment-based
screening
was
carried
out
using
crystals
with
a
pronounced
open
conformation
of
substrate-binding
pocket.
Of
631
soaked
fragments,
total
29
hits
bound
either
in
active
site
(24
hits),
remote
binding
pocket
(three
hits)
or
at
crystal-packing
interfaces
(two
hits).
Notably,
two
fragments
pose
that
sterically
incompatible
more
occluded
crystal
form
were
identified.
Two
isatin-based
electrophilic
covalently
catalytic
cysteine
residue.
The
structures
also
revealed
surprisingly
strong
influence
on
three
published
used
as
positive
controls,
implications
by
crystallography.
Pharmaceuticals,
Год журнала:
2024,
Номер
17(2), С. 198 - 198
Опубликована: Фев. 2, 2024
The
SARS-CoV-2
pandemic
at
the
end
of
2019
had
major
worldwide
health
and
economic
consequences.
Until
effective
vaccination
approaches
were
created,
healthcare
sectors
endured
a
shortage
operative
treatments
that
might
prevent
infection’s
spread.
As
result,
academia
pharmaceutical
industry
prioritized
development
SARS-CoV2
antiviral
medication.
Pyranopyrazoles
have
been
shown
to
play
prominent
function
in
chemistry
drug
sighting
because
their
significant
bioactive
properties.
We
provide
herein
novel
sequence
pyranopyrazoles
annulated
systems
whose
efficacy
cytotoxicity
explored
versus
human
coronavirus
229E
(HCoV-229E)
Vero-E6
cell
lines
as
model
for
Coronaviridae
family.
Fifteen
synthetic
congeners
pointed
out
miscellaneous
efficacies
against
HCoV-229E
with
variable
inhibition
degrees.
Compound
18
showed
high
selectivity
index
(SI
=
12.6)
established
spectacular
inhibitory
capacity
229E.
Compounds
6,
7,
14
exposed
moderate
efficacies.
14,
exhibited
substantial
action
through
replication
phase
reduction
percentages
extending
from
53.6%,
60.7%,
55%
82.2%,
correspondingly.
Likewise,
when
assessed
positive
control
tipranavir
(88.6%),
efficiency
compounds
Mpro
provided
80.4%,
73.1%,
81.4%
up
84.5%,
respectively.
In
silico
studies
performed
investigate
further
biological
activity
target
compounds’
physical
chemical
features,
including
molecular
dynamic
(MD)
simulations,
protein–ligand
docking,
ADME
studies,
density
functional
theory
(DFT)
calculations.
These
inquiries
demonstrated
this
series
metabolically
stable
are
inhibitors
inhibit
viral
protein
may
emerged
COVID-19
curative
option.
