Medicinal Research Reviews,
Journal Year:
2021,
Volume and Issue:
41(4), P. 1965 - 1998
Published: Jan. 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,
Journal Year:
2018,
Volume and Issue:
62(12), P. 5673 - 5724
Published: Dec. 19, 2018
Targeted
covalent
inhibitors
(TCIs)
are
designed
to
bind
poorly
conserved
amino
acids
by
means
of
reactive
groups,
the
so-called
warheads.
Currently,
targeting
noncatalytic
cysteine
residues
with
acrylamides
and
other
α,β-unsaturated
carbonyl
compounds
is
predominant
strategy
in
TCI
development.
The
recent
ascent
drugs
has
stimulated
considerable
efforts
characterize
alternative
warheads
for
covalent-reversible
irreversible
engagement
as
well
acids.
This
Perspective
article
provides
an
overview
warheads-beyond
amides-recently
used
design
targeted
ligands.
Promising
groups
that
have
not
yet
demonstrated
their
utility
development
also
highlighted.
Special
emphasis
placed
on
discussion
reactivity
case
studies
illustrating
applications
medicinal
chemistry
chemical
biology.
Nature Communications,
Journal Year:
2020,
Volume and Issue:
11(1)
Published: Oct. 7, 2020
Abstract
COVID-19,
caused
by
SARS-CoV-2,
lacks
effective
therapeutics.
Additionally,
no
antiviral
drugs
or
vaccines
were
developed
against
the
closely
related
coronavirus,
SARS-CoV-1
MERS-CoV,
despite
previous
zoonotic
outbreaks.
To
identify
starting
points
for
such
therapeutics,
we
performed
a
large-scale
screen
of
electrophile
and
non-covalent
fragments
through
combined
mass
spectrometry
X-ray
approach
SARS-CoV-2
main
protease,
one
two
cysteine
viral
proteases
essential
replication.
Our
crystallographic
identified
71
hits
that
span
entire
active
site,
as
well
3
at
dimer
interface.
These
structures
reveal
routes
to
rapidly
develop
more
potent
inhibitors
merging
covalent
fragment
hits;
series
low-reactivity,
tractable
progressed
discover
improved
binders.
offer
unprecedented
structural
reactivity
information
on-going
structure-based
drug
design
protease.
Journal of Medicinal Chemistry,
Journal Year:
2019,
Volume and Issue:
62(17), P. 7923 - 7940
Published: Aug. 5, 2019
Aberrant
activation
of
Bruton's
tyrosine
kinase
(BTK)
plays
an
important
role
in
pathogenesis
B-cell
lymphomas,
suggesting
that
inhibition
BTK
is
useful
the
treatment
hematological
malignancies.
The
discovery
a
more
selective
on-target
covalent
inhibitor
high
value.
Herein,
we
disclose
and
preclinical
characterization
potent,
selective,
irreversible
as
our
clinical
candidate
by
using
vitro
potency,
selectivity,
pharmacokinetics
(PK),
vivo
pharmacodynamic
for
prioritizing
compounds.
Compound
BGB-3111
(31a,
Zanubrutinib)
demonstrates
(i)
potent
activity
against
excellent
selectivity
over
other
TEC,
EGFR
Src
family
kinases,
(ii)
desirable
ADME,
mice
efficacy
OCI-LY10
xenograft
models.
Frontiers in Pharmacology,
Journal Year:
2018,
Volume and Issue:
9
Published: Sept. 24, 2018
Structure-based
virtual
screening
is
a
widely
used
approach
that
employs
the
knowledge
of
three-
dimensional
structure
target
interest
in
design
new
lead
compounds
from
large-scale
molecular
docking
experiments.
Through
prediction
binding
mode
and
affinity
small
molecule
within
site
interest,
it
possible
to
understand
important
properties
related
process.
Empirical
scoring
functions
are
for
pose
prediction.
Although
performed
with
satisfactory
accuracy,
correct
still
challenging
task
crucial
success
structure-based
There
several
efforts
distinct
fronts
develop
even
more
sophisticated
accurate
models
filtering
ranking
large
libraries
compounds.
This
paper
will
cover
some
recent
successful
applications
methodological
advances,
including
strategies
explore
ligand
entropy
solvent
effects,
training
machine-learning
techniques
use
quantum
mechanics.
Particular
emphasis
be
given
discussion
critical
aspects
further
directions
development
empirical
functions.
Chemical Society Reviews,
Journal Year:
2020,
Volume and Issue:
49(9), P. 2617 - 2687
Published: Jan. 1, 2020
Over
the
past
decade,
covalent
kinase
inhibitors
(CKI)
have
seen
a
resurgence
in
drug
discovery.
Covalency
affords
unique
set
of
advantages
as
well
challenges
relative
to
their
non-covalent
counterpart.
After
reversible
protein
target
recognition
and
binding,
irreversibly
modify
proximal
nucleophilic
residue
on
via
reaction
with
an
electrophile.
To
date,
acrylamide
group
remains
predominantly
employed
electrophile
CKI
development,
its
incorporation
majority
clinical
candidates
FDA
approved
therapies.
Nonetheless,
recent
years
considerable
efforts
ensued
characterize
alternative
electrophiles
that
exhibit
irreversible
or
reversibly
binding
mechanisms
towards
cysteine
thiols
other
amino
acids.
This
review
article
provides
comprehensive
overview
CKIs
reported
literature
over
decade
period,
2007-2018.
Emphasis
is
placed
rationale
behind
warhead
choice,
optimization
approach,
inhibitor
design.
Current
are
also
highlighted,
addition
detailed
analysis
common
trends
themes
observed
within
listed
data
set.
Abstract
3D
pharmacophore
models
are
three‐dimensional
ensembles
of
chemically
defined
interactions
a
ligand
in
its
bioactive
conformation.
They
represent
an
elegant
way
to
decipher
encoded
information
and
have
therefore
become
valuable
tool
drug
design.
In
this
review,
we
provide
overview
on
the
basic
concept
method
summarize
key
studies
for
applying
virtual
screening
mechanistic
protein
functionality.
Moreover,
discuss
recent
developments
field.
The
combination
with
molecular
dynamics
simulations
could
be
quantum
leap
forward
since
these
approaches
consider
macromolecule–ligand
as
dynamic
show
physiologically
relevant
interaction
pattern.
Other
trends
include
efficient
usage
machine
learning
artificial
intelligence
applications
or
freely
accessible
web
servers
modeling.
that
modeling
is
vibrant
field
various
discovery
beyond.
This
article
categorized
under:
Computer
Information
Science
>
Chemoinformatics
Algorithms
Programming
Molecular
Statistical
Mechanics
Interactions
