Journal of the American Chemical Society,
Год журнала:
2023,
Номер
145(5), С. 2711 - 2732
Опубликована: Янв. 27, 2023
Only
around
20%
of
the
human
proteome
is
considered
to
be
druggable
with
small-molecule
antagonists.
This
leaves
some
most
compelling
therapeutic
targets
outside
reach
ligand
discovery.
The
concept
targeted
protein
degradation
(TPD)
promises
overcome
these
limitations.
In
brief,
TPD
dependent
on
small
molecules
that
induce
proximity
between
a
interest
(POI)
and
an
E3
ubiquitin
ligase,
causing
ubiquitination
POI.
this
perspective,
we
want
reflect
current
challenges
in
field,
discuss
how
advances
multiomics
profiling,
artificial
intelligence,
machine
learning
(AI/ML)
will
vital
overcoming
them.
presented
roadmap
discussed
context
degraders
but
equally
applicable
for
other
emerging
proximity-inducing
modalities.
Journal of the American Chemical Society,
Год журнала:
2021,
Номер
143(12), С. 4766 - 4774
Опубликована: Март 18, 2021
Protein–protein
interactions
(PPIs)
intimately
govern
various
biological
processes
and
disease
states
therefore
have
been
identified
as
attractive
therapeutic
targets
for
small-molecule
drug
discovery.
However,
the
development
of
highly
potent
inhibitors
PPIs
has
proven
to
be
extremely
challenging
with
limited
clinical
success
stories.
Herein,
we
report
irreversible
human
double
minute
2
(HDM2)/p53
PPI,
which
employ
a
reactive
N-acyl-N-alkyl
sulfonamide
(NASA)
group
warhead.
Mass-based
analysis
successfully
revealed
kinetics
covalent
inhibition
modification
sites
on
HDM2
N-terminal
α-amine
Tyr67,
both
rarely
seen
in
traditional
inhibitors.
Finally,
demonstrated
prolonged
p53-pathway
activation
more
effective
induction
p53-mediated
cell
death
comparison
noncovalent
inhibitor.
This
study
highlights
potential
NASA
warhead
versatile
electrophile
opens
new
avenues
rational
design
PPI
Current Opinion in Structural Biology,
Год журнала:
2022,
Номер
74, С. 102370 - 102370
Опубликована: Апрель 8, 2022
Protein-protein
interactions
(PPIs)
govern
numerous
cellular
functions
in
terms
of
signaling,
transport,
defense
and
many
others.
Designing
novel
PPIs
poses
a
fundamental
challenge
to
our
understanding
molecular
interactions.
The
capability
robustly
engineer
has
immense
potential
for
the
development
synthetic
biology
tools
protein-based
therapeutics.
Over
last
decades,
efforts
this
area
have
relied
purely
on
experimental
approaches,
but
more
recently,
computational
protein
design
made
important
contributions.
Template-based
approaches
utilize
known
transplant
critical
residues
onto
heterologous
scaffolds.
De
novo
instead
uses
methods
generate
binding
motifs,
allowing
broader
scope
sites
engaged
targets.
Here,
we
review
successful
cases,
giving
an
overview
methodological
used
templated
de
PPI
design.
Briefings in Bioinformatics,
Год журнала:
2022,
Номер
23(4)
Опубликована: Июль 13, 2022
We
construct
a
protein-protein
interaction
(PPI)
targeted
drug-likeness
dataset
and
propose
deep
molecular
generative
framework
to
generate
novel
molecules
from
the
features
of
seed
compounds.
This
gains
inspiration
published
models,
uses
key
associated
with
PPI
inhibitors
as
input
develops
models
for
de
novo
design
inhibitors.
For
first
time,
quantitative
estimation
index
compounds
targeting
was
applied
evaluation
generation
model
PPI-targeted
Our
results
estimated
that
generated
had
better
drug-likeness.
Additionally,
our
also
exhibits
comparable
performance
other
several
state-of-the-art
molecule
models.
The
share
chemical
space
iPPI-DB
demonstrated
by
analysis.
peptide
characterization-oriented
ligand-based
are
explored.
Finally,
we
recommend
this
will
be
an
important
step
forward
therapeutics.
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Апрель 4, 2023
In
drug
discovery,
efficient
screening
of
protein-drug
interactions
(PDIs)
is
hampered
by
the
limitations
current
biophysical
approaches.
Here,
we
develop
a
biological
nanopore
sensor
for
single-molecule
detection
proteins
and
PDIs
using
pore-forming
toxin
YaxAB.
Using
this
YaxAB
nanopore,
demonstrate
label-free,
between
anticancer
Bcl-xL
protein
small-molecule
drugs
as
well
Bak-BH3
peptide.
The
long
funnel-shaped
structure
nanofluidic
characteristics
enable
electro-osmotic
trapping
diverse
folded
high-resolution
monitoring
PDIs.
Distinctive
event
distributions
observed
in
two-dimensional
(ΔI/Io-versus-IN)
plot
illustrate
ability
to
discriminate
individual
bound
from
non-binders.
Taken
together,
our
results
present
robust
platform
ultrasensitive,
PDIs,
opening
up
possibility
low-cost,
highly
discovery
against
targets.
RSC Chemical Biology,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
Nucleic
acids
have
the
potential
to
form
not
only
duplexes,
but
also
various
non-canonical
secondary
structures
in
living
cells.
Structure-
and
sequence-selective
binding
of
small
molecules
is
required
for
their
cellular
applications.
International Journal of Molecular Sciences,
Год журнала:
2025,
Номер
26(7), С. 3117 - 3117
Опубликована: Март 28, 2025
Protein-protein
interactions
(PPIs)
form
an
intricate
cellular
network
known
as
the
interactome,
which
is
essential
for
various
processes,
such
gene
regulation,
signal
transduction,
and
metabolic
pathways.
The
dysregulation
of
this
has
been
closely
linked
to
disease
states.
In
cancer,
these
aberrant
PPIs,
termed
oncogenic
PPIs
(OncoPPIs),
are
involved
in
tumour
formation
proliferation.
Therefore,
inhibition
OncoPPIs
becomes
a
strategy
targeted
cancer
therapy.
Small
molecule
inhibitors
have
dominant
PPI
owing
their
small
size
ability
cross
cell
membranes.
However,
peptide-based
emerged
compelling
alternatives,
offering
distinct
advantages
over
inhibitors.
Peptides,
with
larger
flexible
backbones,
can
effectively
engage
broad
interfaces
PPIs.
Their
high
specificity,
lower
toxicity,
ease
modification
make
them
promising
candidates
Over
past
decade,
significant
advancements
made
developing
This
review
discusses
critical
aspects
targeting
emphasizes
significance
therapy,
explores
using
therapeutic
agents.
It
also
highlights
recent
progress
peptide
design
aimed
at
overcoming
limitations
therapeutics,
comprehensive
overview
current
landscape
potential
treatment.
Journal of Materials Research and Technology,
Год журнала:
2020,
Номер
9(6), С. 15394 - 15411
Опубликована: Окт. 23, 2020
l-asparaginase
is
an
amidohydrolase
enzyme
that
widely
identified
as
one
of
the
most
potential
anti
cancerous
drugs.
Nevertheless,
this
drug
poorly
bioavailable
and
hence
its
pharmaceutical
uses
are
limited.
To
improve
bioactivity,
was
loaded
on
gold
nanoparticles
(GNPs)
along
with
Arg-Gly-Asp
(RGD)
peptide
direct
to
targeted
cancer
cells
aim
enhancing
anticancer
efficiency.
Successful
preparation
GNPs
conjugate
(GNPs-PEG-l-asparaginase-RGD)
verified
delineated
by
employing
UV–VIS
spectrophotometer,
FTIR,
XRD,
FE-SEM,
TEM.
Fourier
Transform
Infrared
(FT-IR),
X-Ray
Diffraction
(XRD),
Field
Emission
Scanning
Electron
Microscopic
(FE-SEM),
Transmission
Microscopy
(TEM).
The
efficiency
target
distribute
in
MCF-7
evaluated
using
high
fluorescent
signals
confirmed
fluorescence
microscopy.
A
variety
parameters
were
tested
investigate
each
compound
toward
vitro.
demonstrated
significant
antioxidant
effects
tumor
targeting
efficacy
distribution
cells.
It
caused
a
decrease
cell
proliferation
rate
clonogenicity
cells,
while
initiating
apoptosis
promoting
cycle
arrest
at
G2/M,
flow
cytometry
analysis.
These
coupled
upregulating
pro-apoptotic
p53
downregulating
anti-apoptotic
Bcl-2,
which
resulted
alleviation
mitochondrial
membrane
(MMP)
and,
thereby,
secretion
cytochrome
c.
outcomes
present
study
propose
feasibility
for
further
development
novel
agent
against
Advances and Applications in Bioinformatics and Chemistry,
Год журнала:
2020,
Номер
Volume 13, С. 11 - 25
Опубликована: Ноя. 1, 2020
Abstract:
It
has
been
noticed
that
the
efficiency
of
drug
development
decreasing
in
past
few
decades.
To
overcome
situation,
protein–protein
interactions
(PPIs)
have
identified
as
new
targets
early
2000.
PPIs
are
more
abundant
human
cells
than
single
proteins
and
play
numerous
important
roles
cellular
processes
including
diseases.
However,
very
different
physicochemical
features
from
conventional
targets,
which
make
targeting
challenging.
Therefore,
now,
only
a
small
number
PPI
inhibitors
approved
or
progressed
to
stage
clinical
trial.
In
this
article,
we
first
overview
previous
works
analyzed
differences
between
with
ligands
drugs
their
binding
pockets.
Then,
constructed
an
up-to-date
list
currently
under
trial
bound
drug–target
structures
available.
Using
dataset,
using
several
scores
druggability.
Druggability
showed
sites
less
druggable
pockets
drugs,
also
indicates
do
not
follow
rules
for
design,
such
Lipinski’s
rule
five.
Our
analyses
suggest
developing
would
be
beneficial
guiding
PPI-drug
discovery.
Keywords:
interaction,
PPI,
discovery