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.
Abstract
Coarse-grained
(CG)
modelling
with
the
Martini
force
field
has
come
of
age.
By
combining
a
variety
bead
types
and
sizes
new
mapping
approach,
newest
version
model
is
able
to
accurately
simulate
large
biomolecular
complexes
at
millisecond
timescales.
In
this
perspective,
we
discuss
possible
applications
3
in
drug
discovery
development
pipelines
highlight
areas
for
future
development.
Owing
its
high
simulation
efficiency
extended
chemical
space,
great
potential
area
design
delivery.
However,
several
aspects
should
be
improved
before
CG
simulations
can
routinely
employed
academic
industrial
settings.
These
include
automatic
parameterisation
protocols
molecule
types,
improvement
backmapping
procedures,
description
protein
flexibility
methodologies
enabling
efficient
sampling.
We
illustrate
our
view
examples
on
key
where
could
give
important
contributions
such
as
drugs
targeting
membrane
proteins,
cryptic
pockets
protein–protein
interactions
soft
delivery
systems.
Acta Pharmaceutica Sinica B,
Год журнала:
2022,
Номер
12(9), С. 3548 - 3566
Опубликована: Март 31, 2022
Molecular
glues
can
specifically
induce
aggregation
between
two
or
more
proteins
to
modulate
biological
functions.
In
recent
years,
molecular
have
been
widely
used
as
protein
degraders.
addition,
however,
play
a
variety
of
vital
roles,
such
complex
stabilization,
interactome
modulation
and
transporter
inhibition,
enabling
challenging
therapeutic
targets
be
druggable
offering
an
exciting
novel
approach
for
drug
discovery.
Since
most
are
identified
serendipitously,
exploration
their
systematic
discovery
rational
design
important.
this
review,
representative
examples
with
various
physiological
functions
divided
into
those
mediating
homo-dimerization,
homo-polymerization
hetero-dimerization
according
modes,
we
attempt
elucidate
mechanisms
action.
particular,
aim
highlight
some
biochemical
techniques
typically
exploited
within
these
studies
classify
them
in
terms
three
stages
glue
development:
starting
point,
optimization
identification.
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.
