PLoS ONE,
Год журнала:
2025,
Номер
20(1), С. e0313094 - e0313094
Опубликована: Янв. 7, 2025
Breast
cancer
remains
a
significant
challenge
in
oncology,
highlighting
the
need
for
alternative
therapeutic
strategies
that
target
necroptosis
to
overcome
resistance
conventional
therapies.
Recent
investigations
into
natural
compounds
have
identified
8,12-dimethoxysanguinarine
(SG-A)
from
Eomecon
chionantha
as
potential
inducer.
This
study
presents
first
computational
exploration
of
SG-A
interactions
with
key
necroptotic
proteins—RIPK1,
RIPK3,
and
MLKL—through
molecular
docking,
dynamics
(MD),
density
functional
theory
(DFT),
electrostatic
(MEP)
analyses.
Molecular
docking
revealed
exhibited
stronger
affinity
MLKL
(-9.40
kcal/mol)
compared
co-crystallized
ligand
(-6.29
kcal/mol),
while
its
RIPK1
(-6.37
RIPK3
(-7.01
was
lower.
MD
simulations
further
demonstrated
stability
within
site,
RMSD
values
stabilizing
between
1.4
3.3
Å
over
300
ns,
indicating
consistent
interaction
pattern.
RMSF
analysis
indicated
preservation
protein
backbone
flexibility,
average
fluctuations
under
1.7
Å.
The
radius
gyration
(Rg)
results
value
~15.3
across
systems,
confirming
role
maintaining
integrity.
Notably,
maintains
two
critical
H-bonds
active
site
MLKL,
reinforcing
interaction.
Principal
component
(PCA)
reduction
MLKL’s
conformational
space
upon
binding,
implying
enhanced
stabilization.
Dynamic
cross-correlation
map
(DCCM)
induced
highly
correlated
motions,
reducing
internal
ligand.
MM-PBSA
binding
efficacy
SG-A,
free
energy
-31.03
±
0.16
kcal/mol
against
surpassing
control
(23.96
0.11
kcal/mol).
In
addition,
individual
residue
contribution
highlighted
interactions,
ARG149
showing
(-176.24
MLKL-SG-A
complex.
DFT
MEP
studies
corroborated
these
findings,
revealing
electronic
structure
is
conducive
stable
characterized
by
narrow
band
gap
(~0.16
units)
distinct
favourable
induction.
conclusion,
has
emerged
compelling
inducer
breast
therapy,
warranting
experimental
validation
fully
realize
potential.
ACS Medicinal Chemistry Letters,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 27, 2025
The
invention
in
this
patent
application
relates
to
2-amino-[1,2,4]triazolo[1,5-a]pyridin
derivatives
represented
generally
herein
as
formula
1.
These
compounds
have
activities
receptor-interacting
protein
kinase
1
(RIPK1)
inhibitors
and
may
potentially
provide
treatment
and/or
prophylaxis
of
inflammatory
neurodegenerative
diseases
associated
with
aberrant
RIPK1
activity
such
ulcerative
colitis,
Crohn's
disease,
psoriasis,
NASH,
heart
failure,
multiple
sclerosis,
amyotrophic
lateral
sclerosis
(ALS),
Alzheimer's
disease.
CNS Neuroscience & Therapeutics,
Год журнала:
2025,
Номер
31(2)
Опубликована: Фев. 1, 2025
ABSTRACT
Background
Vascular
dementia
(VaD)
includes
a
group
of
brain
disorders
that
are
characterized
by
cerebrovascular
pathology.Neuroinflammation,
disruption
the
blood–brain
barrier
(BBB)
permeability,
white
matter
lesions,
and
neuronal
loss
all
significant
pathological
manifestations
VaD
play
key
role
in
disease
progression.
Necroptosis,
also
known
asprogrammed
necrosis,
is
mode
programmed
cell
death
distinct
from
apoptosis
closely
associated
with
ischemic
injury
neurodegenerative
diseases.
Recent
studies
have
shown
necroptosis
exacerbates
BBB
destruction,
activates
neuroinflammation,
promotes
loss,
severely
affects
prognosis.
Results
Conclusions
In
this
review,
we
outline
roles
its
molecular
mechanisms
process
VaD,
particular
focus
on
modulating
neuroinflammation
exacerbating
permeability
elaborate
regulatory
centrally
involved
cells
mediated
tumor
necrosis
factor‐α
VaD.
We
analyze
possibility
specific
strategy
targeting
would
help
inhibit
destruction
With
necroptosis,
study
delved
into
impact
changes
prognosis
to
provide
new
treatment
ideas.
ACS Medicinal Chemistry Letters,
Год журнала:
2024,
Номер
15(4), С. 447 - 448
Опубликована: Апрель 2, 2024
Provided
herein
are
novel
isoxazolidines
as
RIPK1
inhibitors,
pharmaceutical
compositions,
use
of
such
compounds
in
treating
Alzheimer's
disease,
multiple
sclerosis,
and
amyotrophic
lateral
sclerosis
(ALS),
processes
for
preparing
compounds.
ACS Chemical Neuroscience,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 3, 2025
Receptor-interacting
protein
kinase
1
(RIPK1)
serves
as
a
critical
mediator
of
cell
necroptosis
and
represents
promising
therapeutic
target
for
various
human
neurodegenerative
diseases
inflammatory
diseases.
Nonetheless,
the
RIPK1
inhibitors
currently
reported
are
inadequate
clinical
research
due
to
suboptimal
inhibitory
activities
or
lack
selectivity.
Consequently,
there
is
need
discovery
novel
inhibitors.
In
this
study,
we
integrated
deep
learning
model,
specifically
fingerprint
graph
attention
network
(FP-GAT),
with
molecular
docking-based
virtual
screening
identify
potential
from
library
comprising
13
million
compounds.
Out
43
compounds
procured,
two
(designated
24
41)
demonstrated
enzyme
inhibition
activity
exceeding
50%
at
concentration
10
μM
against
RIPK1.
The
half-maximal
concentrations
(IC50)
41
were
determined
be
2.01
2.95
μM,
respectively.
Furthermore,
these
exhibited
protective
effects
in
an
HT-29
model
TSZ-induced
necroptosis,
effective
(EC50)
6.77
compound
68.70
41.
Finally,
dynamics
simulations
binding
free
energy
calculations
conducted
elucidate
mechanism
results
show
that
Met92,
Met95,
Ala155,
Asp156
key
residues
summary,
work
discovered
hit
targeting
RIPK1,
which
can
further
structurally
modified
become
lead
Frontiers in Transplantation,
Год журнала:
2025,
Номер
4
Опубликована: Апрель 24, 2025
This
Part
2
of
a
bipartite
review
commences
with
the
delineation
conceptual
model
outlining
fundamental
role
injury-induced
regulated
cell
death
(RCD)
in
release
DAMPs
that
drive
innate
immune
responses
involved
early
inflammation-related
allograft
dysfunction
and
alloimmune-mediated
rejection.
In
relation
to
this
topic,
focus
is
on
divergent
donor
recipient
dendritic
cells
(DCs),
which
become
immunogenic
presence
regulate
alloimmunity,
but
absence
acquire
tolerogenic
properties
promote
allotolerance.
With
respect
scenario,
proposals
are
then
made
for
leveraging
RCD
as
biomarkers
during
normothermic
regional
perfusion
(NRP)
machine
(NMP)
transplant
organs
from
DCD
donors,
strategy
poised
significantly
enhance
current
policies
assessing
organ
quality.
The
ambitious
goal
target
therapeutically
NRP
NMP,
aiming
profoundly
suppress
subsequently
inflammation
alloimmunity
recipient.
strategic
approach
seeks
prevent
activation
intragraft
including
DCs
reperfusion
recipient,
driven
by
ischemia/reperfusion
DAMPs.
context,
available
inhibitors
various
types
RCD,
well
scavengers
highlighted
their
promising
therapeutic
potential
NMP
settings,
building
proven
efficacy
other
experimental
disease
models.
If
successful,
kind
intervention
should
also
be
considered
application
DBD
donors.
Finally,
drawing
global
insights
into
critical
driving
inflammatory
(allo)immune
responses,
targeting
inhibition
and/or
prevention
donors
-
potentially
holds
transformative
not
only
alleviate
rejection
foster
tolerance.
