bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Окт. 10, 2023
Protein-protein
interactions
(PPIs)
play
a
crucial
role
in
numerous
biochemical
and
biological
processes.
Although
several
structure-based
molecular
generative
models
have
been
developed,
PPI
interfaces
compounds
targeting
PPIs
exhibit
distinct
physicochemical
properties
compared
to
traditional
binding
pockets
small-molecule
drugs.
As
result,
generating
that
effectively
target
PPIs,
particularly
by
considering
complexes
or
interface
hotspot
residues,
remains
significant
challenge.
In
this
work,
we
constructed
comprehensive
dataset
of
with
active
inactive
compound
pairs.
Based
on
this,
propose
novel
framework
tailored
interfaces,
named
GENiPPI.
Our
evaluation
demonstrates
GENiPPI
captures
the
implicit
relationships
between
molecules,
can
generate
these
interfaces.
Moreover,
structurally
diverse
limited
modulators.
To
best
our
knowledge,
is
first
exploration
model
focused
which
could
facilitate
design
The
interface-based
enriches
existing
landscape
(pocket/interface)
model.
Respiratory Research,
Год журнала:
2024,
Номер
25(1)
Опубликована: Авг. 2, 2024
Shortening
of
airway
smooth
muscle
and
bronchoconstriction
are
pathognomonic
for
asthma.
Airway
shortening
occurs
through
calcium-dependent
activation
myosin
light
chain
kinase,
RhoA-dependent
calcium
sensitization,
which
inhibits
phosphatase.
The
mechanism
pro-contractile
stimuli
activate
sensitization
is
poorly
understood.
Our
review
the
literature
suggests
that
G
protein
coupled
receptors
likely
signal
Protein-protein
interaction
(PPI)
modulation
is
a
promising
approach
in
drug
discovery
with
the
potential
to
expand
'druggable'
proteome
and
develop
new
therapeutic
strategies.
While
there
have
been
significant
advancements
methodologies
for
developing
PPI
inhibitors,
relative
scarcity
of
literature
describing
'bottom-up'
development
stabilizers
(Molecular
Glues).
The
hub
protein
14-3-3
its
interactome
provide
an
excellent
platform
exploring
conceptual
approaches
modulation,
including
evolution
chemical
matter
Molecular
Glues.
In
this
study,
we
employed
fragment
extension
strategy
discover
complex
Estrogen
Receptor
alpha-derived
peptide
(ERα).
A
focused
library
analogues
derived
from
amidine-substituted
thiophene
enhanced
affinity
14-3-3/ERα
up
6.2-fold.
Structure-activity
relationship
(SAR)
analysis
underscored
importance
newly
added,
aromatic
side
chain
certain
degree
rigidity.
X-ray
structural
revealed
unique
intermolecular
π-π
stacking
binding
mode
most
active
analogues,
resulting
simultaneous
two
molecules
pocket.
Notably,
analogue
11
displayed
selective
stabilization
complex.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Окт. 10, 2023
Protein-protein
interactions
(PPIs)
play
a
crucial
role
in
numerous
biochemical
and
biological
processes.
Although
several
structure-based
molecular
generative
models
have
been
developed,
PPI
interfaces
compounds
targeting
PPIs
exhibit
distinct
physicochemical
properties
compared
to
traditional
binding
pockets
small-molecule
drugs.
As
result,
generating
that
effectively
target
PPIs,
particularly
by
considering
complexes
or
interface
hotspot
residues,
remains
significant
challenge.
In
this
work,
we
constructed
comprehensive
dataset
of
with
active
inactive
compound
pairs.
Based
on
this,
propose
novel
framework
tailored
interfaces,
named
GENiPPI.
Our
evaluation
demonstrates
GENiPPI
captures
the
implicit
relationships
between
molecules,
can
generate
these
interfaces.
Moreover,
structurally
diverse
limited
modulators.
To
best
our
knowledge,
is
first
exploration
model
focused
which
could
facilitate
design
The
interface-based
enriches
existing
landscape
(pocket/interface)
model.
