Medicinal Research Reviews,
Год журнала:
2021,
Номер
41(4), С. 1965 - 1998
Опубликована: Янв. 18, 2021
Abstract
The
emergence
of
a
variety
coronaviruses
(CoVs)
in
the
last
decades
has
posed
huge
threats
to
human
health.
Especially,
ongoing
pandemic
coronavirus
disease
2019
(COVID‐19)
caused
by
severe
acute
respiratory
syndrome
2
(SARS‐CoV‐2)
led
more
than
70
million
infections
and
over
1.6
deaths
worldwide
past
few
months.
None
efficacious
antiviral
agents
against
CoVs
have
been
approved
yet.
3C‐like
protease
(3CL
pro
)
is
an
attractive
target
for
intervention
due
its
essential
role
processing
polyproteins
translated
from
viral
RNA,
conserved
structural
feature
substrate
specificity
among
spite
sequence
variation.
This
review
focuses
on
all
available
crystal
structures
12
CoV
3CL
s
their
inhibitors,
intends
provide
comprehensive
understanding
this
multiple
aspects
including
features,
specificity,
inhibitor
binding
modes,
importantly,
recapitulate
similarity
diversity
different
structure–activity
relationship
various
types
inhibitors.
Such
attempt
could
gain
deep
insight
into
inhibition
mechanisms
drive
future
structure‐based
drug
discovery
targeting
s.
Journal of Medicinal Chemistry,
Год журнала:
2022,
Номер
65(19), С. 12500 - 12534
Опубликована: Сен. 28, 2022
The
viral
main
protease
is
one
of
the
most
attractive
targets
among
all
key
enzymes
involved
in
SARS-CoV-2
life
cycle.
Covalent
inhibition
cysteine145
MPRO
with
selective
antiviral
drugs
will
arrest
replication
process
virus
without
affecting
human
catalytic
pathways.
In
this
Perspective,
we
analyzed
silico,
vitro,
and
vivo
data
representative
examples
covalent
inhibitors
reported
literature
to
date.
particular,
studied
molecules
were
classified
into
eight
different
categories
according
their
reactive
electrophilic
warheads,
highlighting
differences
between
reversible/irreversible
mechanism
inhibition.
Furthermore,
analyses
recurrent
pharmacophoric
moieties
stereochemistry
chiral
carbons
reported.
noncovalent
silico
protocols,
provided
would
be
useful
for
scientific
community
discover
new
more
efficient
inhibitors.
Signal Transduction and Targeted Therapy,
Год журнала:
2024,
Номер
9(1)
Опубликована: Дек. 5, 2024
Abstract
Protein-protein
interactions
(PPIs)
are
fundamental
to
cellular
signaling
and
transduction
which
marks
them
as
attractive
therapeutic
drug
development
targets.
What
were
once
considered
be
undruggable
targets
have
become
increasingly
feasible
due
the
progress
that
has
been
made
over
last
two
decades
rapid
technological
advances.
This
work
explores
influence
of
innovations
on
PPI
research
development.
Additionally,
diverse
strategies
for
discovering,
modulating,
characterizing
PPIs
their
corresponding
modulators
examined
with
aim
presenting
a
streamlined
pipeline
advancing
PPI-targeted
therapeutics.
By
showcasing
carefully
selected
case
studies
in
modulator
discovery
development,
we
illustrate
efficacy
various
identifying,
optimizing,
overcoming
challenges
associated
design.
The
valuable
lessons
insights
gained
from
identification,
optimization,
approval
discussed
demonstrating
transitioned
beyond
early-stage
now
represent
prime
opportunity
significant
potential.
examples
encompass
those
developed
cancer,
inflammation
immunomodulation,
well
antiviral
applications.
perspective
aims
establish
foundation
effective
targeting
modulation
using
pave
way
future
Chemistry - A European Journal,
Год журнала:
2019,
Номер
26(6), С. 1196 - 1237
Опубликована: Авг. 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.
Biochemistry,
Год журнала:
2018,
Номер
57(24), С. 3326 - 3337
Опубликована: Апрель 24, 2018
Covalent
enzyme
inhibitors
are
widely
applied
as
biochemical
tools
and
therapeutic
agents.
As
a
complement
to
categorization
of
these
by
reactive
group
or
modification
site,
we
present
mechanism,
which
highlights
common
advantages
disadvantages
inherent
each
approach.
Established
categories
for
reversible
irreversible
covalent
inhibition
reviewed
with
representative
examples
given
class,
including
inhibitors,
slow
substrates,
residue-specific
reagents,
affinity
labels
(classical,
quiescent,
photoaffinity),
mechanism-based
inactivators.
The
relationships
proteomic
profiling
probes
(activity-based
reactivity-based)
well
complementary
approaches
such
prodrug
soft
drug
design
also
discussed.
A
wide
variety
strategies
used
balance
reactivity
selectivity
in
the
inhibitors.
Use
shared
terminology
is
encouraged
clearly
convey
mechanisms,
relate
them
prior
use
enzymology,
facilitate
development
more
effective
