Angewandte Chemie International Edition,
Journal Year:
2018,
Volume and Issue:
58(4), P. 957 - 966
Published: July 19, 2018
Selective
covalent
modification
of
a
targeted
protein
is
powerful
tool
in
chemical
biology
and
drug
discovery,
with
applications
ranging
from
identification
characterization
proteins
their
functions
to
the
development
inhibitors.
Most
ligands
contain
an
affinity
motif
electrophilic
warhead
that
reacts
nucleophilic
residue
protein.
Because
prone
react
modify
off-target
nucleophiles,
its
reactivity
should
be
balanced
carefully
maximize
target
selectivity.
Arylfluorosulfates
have
recently
emerged
as
latent
electrophiles
for
selective
labeling
context-specific
tyrosine
lysine
residues
pockets.
Here,
we
review
recent
but
intense
introduction
arylfluorosulfates
into
arsenal
available
warheads
proteins.
We
highlight
untapped
potential
this
functional
group
use
discovery.
Journal of Chemical Information and Modeling,
Journal Year:
2017,
Volume and Issue:
57(12), P. 3124 - 3137
Published: Nov. 13, 2017
Targeted
covalent
inhibition
is
an
established
approach
for
increasing
the
potency
and
selectivity
of
potential
drug
candidates,
as
well
identifying
potent
selective
tool
compounds
target
validation
studies.
It
evident
that
identification
reversible
recognition
elements
essential
inhibition,
but
this
must
also
be
achieved
with
appropriate
level
inherent
reactivity
reactive
functionality
(or
"warhead").
Structural
changes
increase
or
decrease
warhead
reactivity,
guided
by
methods
to
predict
effect
those
changes,
have
tune
negate
issues
related
and/or
toxicity.
The
half-life
adduct
formation
glutathione
(GSH
t1/2)
a
useful
assay
measuring
cysteine-targeting
warheads
limited
synthesized
molecules.
In
manuscript
we
assess
ability
several
experimental
computational
approaches
GSH
t1/2
range
cysteine
targeting
warheads,
including
novel
method
based
on
pKa.
Furthermore,
matched
molecular
pairs
analysis
has
been
performed
against
our
internal
compound
collection,
revealing
structure–activity
relationships
between
selection
different
warheads.
These
observations
prediction
will
valuable
in
design
new
inhibitors
desired
levels
reactivity.
Journal of Medicinal Chemistry,
Journal Year:
2017,
Volume and Issue:
60(9), P. 3656 - 3671
Published: April 14, 2017
Pharmacological
inhibition
of
NLRP3
inflammasome
activation
may
offer
a
new
option
in
the
treatment
inflammatory
bowel
disease.
In
this
work,
we
report
design,
synthesis,
and
biological
screening
series
acrylate
derivatives
as
inhibitors.
The
vitro
determination
reactivity,
cytotoxicity,
ATPase
inhibition,
antipyroptotic
properties
allowed
selection
11
(INF39),
nontoxic,
irreversible
inhibitor
able
to
decrease
interleukin-1β
release
from
macrophages.
Bioluminescence
resonance
energy
transfer
experiments
proved
that
compound
was
directly
interfere
with
cells.
vivo
studies
confirmed
ability
selected
lead
alleviate
effects
colitis
induced
by
2,4-dinitrobenzenesulfonic
acid
rats
after
oral
administration.
Chemistry - A European Journal,
Journal Year:
2019,
Volume and Issue:
26(6), P. 1196 - 1237
Published: Aug. 20, 2019
Abstract
All
pharmaceutical
products
contain
organic
molecules;
the
source
may
be
a
natural
product
or
fully
synthetic
molecule,
combination
of
both.
Thus,
it
follows
that
chemistry
underpins
both
existing
and
upcoming
products.
The
reverse
relationship
has
also
affected
synthesis,
changing
its
landscape
towards
increasingly
complex
targets.
This
Review
article
sets
out
to
give
concise
appraisal
this
symbiotic
between
drug
discovery,
along
with
discussion
design
concepts
highlighting
key
milestones
journey.
In
particular,
criteria
for
high‐quality
compound
library
enabling
efficient
virtual
navigation
chemical
space,
as
well
rise
fall
exploration
(such
combinatorial
chemistry;
diversity‐,
biology‐,
lead‐,
fragment‐oriented
syntheses;
DNA‐encoded
libraries)
are
critically
surveyed.
Angewandte Chemie International Edition,
Journal Year:
2018,
Volume and Issue:
58(4), P. 957 - 966
Published: July 19, 2018
Selective
covalent
modification
of
a
targeted
protein
is
powerful
tool
in
chemical
biology
and
drug
discovery,
with
applications
ranging
from
identification
characterization
proteins
their
functions
to
the
development
inhibitors.
Most
ligands
contain
an
affinity
motif
electrophilic
warhead
that
reacts
nucleophilic
residue
protein.
Because
prone
react
modify
off-target
nucleophiles,
its
reactivity
should
be
balanced
carefully
maximize
target
selectivity.
Arylfluorosulfates
have
recently
emerged
as
latent
electrophiles
for
selective
labeling
context-specific
tyrosine
lysine
residues
pockets.
Here,
we
review
recent
but
intense
introduction
arylfluorosulfates
into
arsenal
available
warheads
proteins.
We
highlight
untapped
potential
this
functional
group
use
discovery.
