Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Март 15, 2023
Abstract
Cannabinoid
CB
2
receptor
(CB
R)
agonists
are
investigated
as
therapeutic
agents
in
the
clinic.
However,
their
molecular
mode-of-action
is
not
fully
understood.
Here,
we
report
discovery
of
LEI-102,
a
R
agonist,
used
conjunction
with
three
other
CBR
ligands
(APD371,
HU308,
and
CP55,940)
to
investigate
selective
activation
by
binding
kinetics,
site-directed
mutagenesis,
cryo-EM
studies.
We
identify
key
residues
for
activation.
Highly
lipophilic
HU308
endocannabinoids,
but
more
polar
APD371,
CP55,940,
reach
pocket
through
membrane
channel
TM1-TM7.
Favorable
physico-chemical
properties
LEI-102
enable
oral
efficacy
chemotherapy-induced
nephropathy
model.
This
study
delineates
mechanism
highlights
role
lipophilicity
engagement.
may
have
implications
GPCR
drug
design
sheds
light
on
endogenous
ligands.
ACS Central Science,
Год журнала:
2024,
Номер
10(5), С. 956 - 968
Опубликована: Март 11, 2024
We
report
a
blueprint
for
the
rational
design
of
G
protein
coupled
receptor
(GPCR)
ligands
with
tailored
functional
response.
The
present
study
discloses
structure-based
cannabinoid
type
2
(CB2R)
selective
inverse
agonists
(S)-1
and
(R)-1,
which
were
derived
from
privileged
agonist
HU-308
by
introduction
phenyl
group
at
gem-dimethylheptyl
side
chain.
Epimer
(R)-1
exhibits
high
affinity
CB2R
Kd
=
39.1
nM
serves
as
platform
synthesis
wide
variety
probes.
Notably,
first
time
these
fluorescent
probes
retain
their
functionality,
affinity,
selectivity
independent
linker
fluorophore
substitution.
Ligands
(S)-1,
derivatives
act
in
CB2R-mediated
cAMP
well
recruitment
assays
do
not
trigger
β-arrestin-receptor
association.
Furthermore,
no
activation
was
detected
live
cell
ERK1/2
phosphorylation
Ca2+-release
assays.
Confocal
fluorescence
imaging
experiments
(R)-7
(Alexa488)
(R)-9
(Alexa647)
employing
BV-2
microglial
cells
visualized
expressed
endogenous
levels.
Finally,
molecular
dynamics
simulations
corroborate
initial
docking
data
restrict
movement
toggle
switch
Trp2586.48
thereby
stabilize
its
inactive
state.
Diabetology & Metabolic Syndrome,
Год журнала:
2024,
Номер
16(1)
Опубликована: Фев. 15, 2024
Cannabinoid
receptors
are
components
of
the
endocannabinoid
system
that
affect
various
physiological
functions.
We
aim
to
investigate
effect
cannabinoid
receptor
modulation
on
kidney
disease.
PubMed,
Web
Science
databases,
and
EMBASE
were
searched.
Articles
selection,
data
extraction
quality
assessment
independently
performed
by
two
investigators.
The
SYRCLE's
RoB
tool
was
used
assess
risk
study
bias,
pooled
SMD
using
a
random-effect
model
95%
CIs
calculated.
Subgroup
analyses
conducted
in
preselected
subgroups,
publication
bias
evaluated.
compared
effects
CB1
CB2
antagonists
and/or
knockout
agonists
genetic
regulation
renal
function,
blood
glucose
levels,
body
weight,
pathological
damage-related
indicators
different
models
chronic
acute
injury.
blockade
or
could
significantly
reduce
urea
nitrogen
[SMD,-
1.67
(95%
CI
-
2.27
1.07)],
serum
creatinine
[SMD,
1.88
2.91
0.85)],
albuminuria
1.60
2.16
1.04)]
dysfunction
animals
with
control
group.
activation
group
0.97
1.83
0.11)]
2.43
4.63
0.23)]
results
suggest
targeting
receptors,
particularly
agonists,
can
improve
function
inflammatory
responses,
exerting
protective
maintaining
therapeutic
potential
types
Computers in Biology and Medicine,
Год журнала:
2024,
Номер
175, С. 108486 - 108486
Опубликована: Апрель 16, 2024
In
this
paper,
we
introduce
DeLA-DrugSelf,
an
upgraded
version
of
DeLA-Drug
[J.
Chem.
Inf.
Model.
62
(2022)
1411-1424],
which
incorporates
essential
advancements
for
automated
multi-objective
de
novo
design.
Unlike
its
predecessor,
relies
on
SMILES
notation
molecular
representation,
DeLA-DrugSelf
employs
a
novel
and
robust
representation
string
named
SELFIES
(SELF-referencing
embedded
string).
The
generation
process
in
not
only
involves
substitutions
to
the
initial
representing
starting
query
molecule
but
also
insertions
deletions.
This
enhancement
makes
significantly
more
adept
at
executing
data-driven
scaffold
decoration
lead
optimization
strategies.
Remarkably,
explicitly
addresses
SELFIES-related
collapse
issue,
considering
collapse-free
compounds
during
generation.
These
undergo
rigorous
quality
metrics
evaluation,
highlighting
substantial
terms
drug-likeness,
uniqueness,
novelty
compared
molecules
generated
by
previous
algorithm.
To
evaluate
potential
as
mutational
operator
within
genetic
algorithm
framework
optimization,
employed
fitness
function
based
Pareto
dominance.
Our
objectives
focused
target-oriented
properties
aimed
optimizing
known
cannabinoid
receptor
2
(CB2R)
ligands.
results
obtained
indicate
that
available
user-friendly
web
platform
(https://www.ba.ic.cnr.it/softwareic/delaself/),
can
effectively
contribute
bioactive
user-defined
parameters.
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(12), С. 6708 - 6708
Опубликована: Июнь 18, 2024
Stroke
is
one
of
the
leading
causes
death.
It
not
only
affects
adult
people
but
also
many
children.
estimated
that,
every
year,
15
million
suffer
a
stroke
worldwide.
Among
them,
5
die,
while
are
left
permanently
disabled.
In
this
sense,
research
to
find
new
treatments
should
be
accompanied
with
therapies
combat
neuronal
death
and
avoid
developing
cognitive
impairment
dementia.
Phytocannabinoids
among
compounds
that
have
been
used
by
mankind
for
longest
period
history.
Their
beneficial
effects
such
as
pain
regulation
or
neuroprotection
widely
known
make
them
possible
therapeutic
agents
high
potential.
These
bind
cannabinoid
receptors
CB
Communications Biology,
Год журнала:
2023,
Номер
6(1)
Опубликована: Май 5, 2023
Abstract
Design
of
cannabinergic
subtype
selective
ligands
is
challenging
because
high
sequence
and
structural
similarities
cannabinoid
receptors
(CB
1
CB
2
).
We
hypothesize
that
the
selectivity
designed
can
be
explained
by
ligand
binding
to
conformationally
distinct
states
between
receptors.
Analysis
~
700
μ
s
unbiased
simulations
using
Markov
state
models
VAMPnets
identifies
distinctions
activation
mechanism
both
Structural
dynamic
comparisons
metastable
intermediate
allow
us
observe
distinction
in
pocket
volume
change
during
activation.
Docking
analysis
reveals
only
a
few
show
affinity
towards
agonists.
In
contrast,
all
similar
for
these
These
results
mechanistically
explain
agonists
deciphering
ACS Pharmacology & Translational Science,
Год журнала:
2024,
Номер
7(5), С. 1348 - 1363
Опубликована: Апрель 25, 2024
Microglia
are
resident
immune
cells
of
the
central
nervous
system
(CNS)
and
propagate
inflammation
following
damage
to
CNS,
including
retina.
Proliferative
vitreoretinopathy
(PVR)
is
a
condition
that
can
emerge
retinal
detachment
characterized
by
severe
microglial
proliferation.
The
type
2
cannabinoid
receptor
(CB2)
an
emerging
pharmacological
target
suppress
microglial-mediated
when
eyes
or
brain
damaged.
CB2-knockout
mice
have
exacerbated
pathology
during
experimental
PVR.
We
aimed
assess
anti-inflammatory
effects
CB2
stimulation
in
context
also
explore
mechanistic
roles
microglia
function.
To
CB2,
we
used
highly
selective
agonist,
HU-308,
as
well
its
enantiomer,
HU-433,
which
putative
agonist.
First,
β-arrestin2
Gαi
recruitment
was
measured
compare
activation
human
vitro
heterologous
expression
system.
Both
agonists
were
then
utilized
mouse
model
PVR,
on
damage,
inflammation,
cell
death
assessed.
Finally,
determine
HU-308
HU-433
phagocytosis,
cytokine
release,
migration,
intracellular
signaling.
observed
more
strongly
recruited
both
compared
HU-433.
Stimulation
with
either
drug
effectively
blunted
LPS-
IFNγ-mediated
signaling
NO
TNF
release
from
microglia.
Furthermore,
drugs
reduced
IL-6
accumulation,
total
caspase-3
cleavage,
induction
Ultimately,
this
work
supports
valuable
for
associated
infection
sterile
retinopathy,
although
magnitude
effector
may
not
be
predictive
capacity.