ACS Chemical Neuroscience,
Год журнала:
2024,
Номер
16(1), С. 16 - 29
Опубликована: Дек. 11, 2024
Positive
allosteric
modulation
of
the
mu-opioid
receptor
is
a
promising
strategy
to
address
ever-growing
problem
acute
and
chronic
pain
management.
modulators
(PAMs)
could
be
employed
enhance
efficacy
endogenous
opioid
peptides
degree
that
provides
relief
without
need
for
traditional
drugs.
Alternatively,
PAMs
might
used
action
drugs
so
provide
an
opioid-sparing
effect,
allowing
use
lower
doses
agonists
potentially
decreasing
associated
side
effects.
BMS-986122
(2-(3-bromo-4-methoxyphenyl)-3-[(4-chlorophenyl)-sulfonyl]-thiazolidine)
has
been
previously
identified
as
PAM
receptor.
In
present
work,
we
have
designed
synthesized
33
analogs
explore
structure–activity
relationships
this
scaffold
confirm
its
mechanism
action.
Among
several
newly
modulators,
most
compound
(14b)
had
improved
activity
increase
in
vitro
potency
standard
agonist
DAMGO
showed
vivo
mice
antinociceptive
morphine.
Trends in Pharmacological Sciences,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
Activation
of
the
μ
opioid
receptor
(MOR)
can
give
analgesia,
but
also
has
dangerous
side
effects.
Drugs
that
target
MOR
through
an
allosteric
site,
meaning
they
bind
outside
usual
pocket,
present
a
novel
mode
activation
with
different
pharmacology
relative
to
orthosteric
drugs.
Recent
structural
studies
valuable
new
information
on
how
modulators
interact
MOR.
G-protein-coupled
receptors
(GPCRs)
transmit
an
extracellular
chemical/biological
signal
across
the
cell
membrane,
stimulating
array
of
intracellular
signaling
cascades.
Canonically,
these
molecules
bind
to
endogenous
ligand
pocket
(orthosteric
pocket),
which
stabilizes
either
active
or
inactive
conformational
ensemble
receptor.
However,
recent
structural
evidence
indicates
that
small
can
mediate
protein–protein
interactions
between
GPCR
and
their
transducers.
These
are
reminiscent
molecular
glues
be
powerful
tools
for
modulating
bias.
In
this
Perspective,
we
will
investigate
current
information
available
on
how
they
modulate
We
also
examine
prospects
drug/probe
design.
Royal Society of Chemistry eBooks,
Год журнала:
2025,
Номер
unknown, С. 1 - 16
Опубликована: Фев. 21, 2025
DNA-encoded
library
(DEL)
selection
is
typically
an
affinity-based
process
that
encompasses
the
incubation
of
DELs
with
a
target,
separation
compounds
bind
target
from
those
do
not
bind,
amplification
and
sequencing
DNA
barcodes,
decoding
to
reveal
chemical
structures
binders.
DEL
technology
has
had
notable
impact
in
drug
discovery
various
projects
progressing
into
different
stages
development
clinical
trials.
methodology
allows
for
ultra-high
throughput
screening,
permitting
exploration
broad
diversity
rapid
identification
hits
exhibit
desired
effects
specific
targets.
have
been
successfully
employed
small
molecules
targeting
variety
pharmaceutical
targets,
including
proteins
nucleic
acids.
This
approach
expedited
tool
probe
biological
processes
hit
progressed
candidates,
thereby
facilitating
process.
In
this
chapter,
we
provide
overview
affinity
strategies
achievements
selections
on
types.
Chemical Reviews,
Год журнала:
2024,
Номер
124(22), С. 12551 - 12572
Опубликована: Ноя. 7, 2024
DNA-encoded
library
(DEL)
technology
is
a
powerful
platform
for
the
efficient
identification
of
novel
chemical
matter
in
early
drug
discovery
process
enabled
by
parallel
screening
vast
libraries
encoded
small
molecules
through
affinity
selection
and
deep
sequencing.
While
DEL
selections
provide
rich
data
sets
computational
discovery,
underlying
technical
factors
influencing
remain
incompletely
understood.
This
review
systematically
examines
key
parameters
affecting
information
their
impact
on
hit
triaging
machine
learning
integration.
The
need
rigorous
handling
interpretation
emphasized,
with
standardized
methods
being
critical
success
DEL-based
approaches.
Major
challenges
include
relationship
between
sequence
counts
binding
affinities,
frequent
hitters,
influence
such
as
inhomogeneous
composition,
DNA
damage,
linkers
modes.
Experimental
artifacts,
those
caused
protein
immobilization
matrix
effects,
further
complicate
interpretation.
Recent
advancements
using
to
denoise
predict
candidates
are
highlighted.
offers
practical
guidance
adopting
best
practices
integrating
robust
methodologies,
comprehensive
analysis,
tools
improve
accuracy
efficacy
DEL-driven
discovery.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 15, 2024
Abstract
G
protein-coupled
receptors
(GPCRs)
play
pivotal
roles
in
cellular
signaling
and
represent
prominent
drug
targets.
Structural
elucidation
of
GPCRs
is
crucial
for
discovery
efforts.
However,
structural
studies
remain
challenging,
particularly
inactive
state
structures,
which
often
require
extensive
protein
engineering.
Here,
we
present
a
de
novo
design
strategy
termed
“click
fusion”
generating
fusion
proteins
to
facilitate
GPCR
studies.
Our
method
involves
the
rational
structurally
stable
domains
rigidly
linked
GPCRs.
The
resulting
enhances
thermostability
target
aids
determining
structures
via
cryo-electron
microscopy
(cryo-EM).
We
further
demonstrate
that
designed
can
be
transferred
among
similar
with
minor
adjustments
linker
region.
study
introduces
promising
approach
facilitating
advancing
