Integrative bioinformatics analysis reveals CGAS as a ferroptosis-related signature gene in sepsis and screens the potential natural inhibitors of CGAS
International Journal of Biological Macromolecules,
Год журнала:
2025,
Номер
unknown, С. 139778 - 139778
Опубликована: Янв. 1, 2025
Язык: Английский
Identification of Novel HPK1 Hit Inhibitors: From In Silico Design to In Vitro Validation
International Journal of Molecular Sciences,
Год журнала:
2025,
Номер
26(9), С. 4366 - 4366
Опубликована: Май 4, 2025
Hematopoietic
progenitor
kinase
1
(HPK1),
a
negative
regulator
of
T-cells,
B-cells,
and
dendritic
cells,
has
gained
attention
in
antitumor
immunotherapy
research
over
the
past
decade.
No
HPK1
inhibitor
yet
reached
clinical
approval,
largely
due
to
selectivity
drug-like
limitations.
Leveraging
available
structural
insights
into
HPK1,
we
conducted
rational
hit
identification
using
structure-based
virtual
screening
600,000
molecules
from
ASINEX
OTAVA
databases.
A
series
molecular
docking
studies,
vitro
assays,
dynamics
simulations
were
identify
viable
hits.
This
approach
resulted
two
promising
novel
scaffolds,
4H-Pyrido[1,2-a]
thieno[2,3-d]
pyrimidin-4-one
(ISR-05)
quinolin-2(1H)-one
(ISR-03),
neither
which
previously
been
reported
as
an
inhibitor.
ISR-05
ISR-03
exhibited
IC50
values
24.2
±
5.07
43.9
0.134
µM,
respectively,
inhibition
assays.
These
hits
constitute
tractable
starting
points
for
future
hit-to-lead
optimization
aimed
at
developing
more
effective
inhibitors
cancer
therapy.
Язык: Английский
Discovery of novel GluN1/GluN3A NMDA receptor inhibitors using a deep learning-based method
Acta Pharmacologica Sinica,
Год журнала:
2025,
Номер
unknown
Опубликована: Май 12, 2025
Язык: Английский
Exploiting subtractive genomics to identify novel drug targets and new immunogenic candidates against Bordetella pertussis: an in silico study
Frontiers in Bioinformatics,
Год журнала:
2025,
Номер
5
Опубликована: Май 13, 2025
Bordetella
pertussis,
the
causative
agent
of
whooping
cough,
remains
a
significant
global
health
concern
despite
widespread
availability
vaccines.
The
persistent
reemergence
pertussis
is
driven
by
bacterium's
ongoing
genomic
evolution,
shifting
epidemiological
patterns,
and
limitations
in
current
vaccine
strategies.
These
challenges
highlight
urgent
need
to
identify
novel
drug
targets
immunogenic
candidates
enhance
therapeutic
preventive
measures
against
B.
pertussis.
Identification
detection
factors
as
potential
were
performed.
Cytoplasmic
proteins
evaluated
for
their
similarity
human
proteome,
metabolic
pathways,
gut
microbiota.
On
other
hand,
surface-exposed
using
reverse
vaccinology
approach.
A
multi-epitope
(MEV)
was
designed
based
on
linear
B-cell
epitopes
three
autotransporters
beta
domain
SphB2
scaffold
MEV.
Molecular
docking,
immune
simulation
results,
molecular
dynamics
simulations
performed
evaluate
binding
affinity
feasibility
interaction
between
chimeric
MEVs
receptors.
Six
identified
excellent
targets,
including
elongation
factor
P
(WP_003810194.1),
Aspartate
kinase
(WP_010930633.1),
50S
ribosomal
protein
L21
(WP_003807462.1),
Homoserine
dehydrogenase
(WP_003813074.1),
Carboxynorspermidine
decarboxylase
(WP_003814461.1),
PTS
sugar
transporter
subunit
IIA
(WP_010929966.1).
nine
proteins,
BapA
(WP_010930805.1),
BrkA
(WP_010931506.1),
(WP_041166323.1),
TcfA
(WP_010930243.1),
FliK
(WP_041166144.1),
Fimbrial
(WP_010930199.1),
TolA
(WP_010931418.1),
DD-metalloendopeptidase
(WP_003811022.1),
an
I78
family
peptidase
inhibitor
(WP_003812179.1).
SphB2-based
MEV
six
extracellular
loops
autotransporters.
TLR2,
TLR4,
HLA-DR-B
computationally
confirmed
dynamics.
It
appears
that
involved
translation
metabolism
can
be
considered
targets.
Furthermore,
this
study
highlights
autotransporter
promising
There
no
doubt
experimental
work
should
conducted
confirm
results
future.
Язык: Английский
On the application of artificial intelligence in virtual screening
Expert Opinion on Drug Discovery,
Год журнала:
2025,
Номер
unknown
Опубликована: Май 19, 2025
Artificial
intelligence
(AI)
has
emerged
as
a
transformative
tool
in
drug
discovery,
particularly
virtual
screening
(VS),
which
is
crucial
initial
step
identifying
potential
candidates.
This
article
highlights
the
significance
of
AI
revolutionizing
both
ligand-based
(LBVS)
and
structure-based
(SBVS)
approaches,
streamlining
enhancing
discovery
process.
The
authors
provide
an
overview
applications
with
focus
on
LBVS
SBVS
approaches
utilized
prospective
cases
where
new
bioactive
molecules
were
identified
experimentally
validated.
Discussion
includes
use
quantitative
structure-activity
relationship
(QSAR)
modeling
for
LBVS,
well
its
role
techniques
such
molecular
docking
dynamics
simulations.
based
literature
searches
all
studies
published
up
to
March
2025.
rapidly
transforming
VS
by
leveraging
increasing
amounts
experimental
data
expanding
scalability.
These
innovations
promise
enhance
efficiency
precision
across
yet
challenges
curation,
rigorous
validation
models,
efficient
integration
methods
remain
critical
realizing
AI's
full
discovery.
Язык: Английский
Piezoelectric Molecular Selection Pump Based on Stokes’ Principle
ACS Applied Engineering Materials,
Год журнала:
2025,
Номер
unknown
Опубликована: Май 25, 2025
Язык: Английский
Allosteric covalent inhibition of TOE1 as potential unexplored anti-cancer target: structure-based virtual screening and covalent molecular dynamics analysis
Journal of Receptors and Signal Transduction,
Год журнала:
2024,
Номер
44(3), С. 97 - 106
Опубликована: Май 3, 2024
Cancer
remains
a
formidable
challenge
in
therapeutic
development
owing
to
its
complex
molecular
mechanisms
and
resistance
conventional
treatments.
Recent
evidence
suggests
that
TOE1
may
play
role
cancer
progression,
making
it
an
attractive
target
for
interventions,
nevertheless,
very
limited
research
literature
has
explored
the
potential
of
inhibitors
as
anti-cancer.
Herein,
by
exploring
library
13,900
cysteine-targeted
covalent
via
comprehensive
virtual
screening
process,
we
sought
identify
compounds
could
be
developed
into
effective
therapies
against
TOE1.
The
were
first
screened
based
on
their
binding
affinity,
followed
compliance
with
drug-like
properties,
finally,
modeling
reactive
cysteine
(Cys80).
A
total
66
compounds,
28
3
found
have
higher
affinities,
optimum
drug-likeness,
docking
scores,
respectively,
than
reference
compound.
top
three
0462,
2204,
7034,
demonstrated
favorable
interaction
profiles,
dynamics,
free
energetics,
per-residue
energy
contributions
compared
Notably,
compound
0462
contributed
highest
significantly
enhanced
stability
rigidity
TOE1,
while
restricting
residue
flexibility.
This
study
provides
account
mechanics
underpinning
inhibition
providing
compelling
case
further
investigation
translation
inhibitors,
particularly
novel
therapeutics
cancer.
Язык: Английский
Antitrypanosomal Potential of Chalcone‐Based Ursolic Acid Derivatives via Ligand‐Based Virtual Screening, DMPK Analyses, Molecular Dynamics Simulation, and MM/GBSA Binding Energy
ChemistrySelect,
Год журнала:
2024,
Номер
9(44)
Опубликована: Ноя. 1, 2024
Abstract
Chagas
disease,
caused
by
the
protozoan
parasite
Trypanosoma
cruzi
and
transmitted
mainly
triatomine
insects,
represents
a
significant
challenge
to
public
health,
especially
in
impoverished
regions.
Current
treatments,
such
as
benznidazole
nifurtimox,
have
limitations,
including
serious
side
effects
reduced
efficacy
chronic
phase.
This
work
aims
evaluate
antitrypanosomal
activity
of
ursolic
acid‐derived
chalcones
(UACD)
using
ligand‐based
virtual
screening
approach.
To
this
end,
series
independent
molecular
docking
simulations
were
carried
out
(via
AutoDock
Vina
code)
with
proliferation
cycle
enzymes
TcGAPDH
cruzain.
The
most
favorable
candidates
underwent
drug
metabolism
pharmacokinetics
(DMPK)
analyses
dynamics
(MD)
estimate
pharmacokinetic
pharmacodynamic
profile.
Molecular
showed
that
UACD
derivatives
better
specificity
for
enzyme,
emphasizing
acid
UACD3
(affinity
energy
=
−9.4
kcal/mol
each).
DMPK
prediction
present
viable
apparent
permeability
(
P
app
)
promotes
an
excellent
absorbed
fraction
(in
10⁻⁶
cm/s).
MD
derivative
free
when
binding
enzyme
(−13.27
±
1.87
kcal/mol)
interacting
active
site
residues
Cys166
Thr167.
However,
both
ligands
appear
be
alternative
therapies
treating
disease.
Язык: Английский