Essays in Biochemistry,
Journal Year:
2017,
Volume and Issue:
61(5), P. 453 - 464
Published: Nov. 8, 2017
It
is
over
20
years
since
the
first
fragment-based
discovery
projects
were
disclosed.
The
methods
are
now
mature
for
most
‘conventional’
targets
in
drug
such
as
enzymes
(kinases
and
proteases)
but
there
has
also
been
growing
success
on
more
challenging
targets,
disruption
of
protein–protein
interactions.
main
application
to
identify
tractable
chemical
startpoints
that
non-covalently
modulate
activity
a
biological
molecule.
In
this
essay,
we
overview
current
practice
discuss
how
they
have
had
an
impact
lead
–
generating
large
number
fragment-derived
compounds
clinical
trials
two
medicines
treating
patients.
addition,
some
recent
applications
biology
providing
tools
investigate
molecules,
mechanisms
systems.
Much
of
our
current
understanding
how
small-molecule
ligands
interact
with
proteins
stems
from
X-ray
crystal
structures
determined
at
cryogenic
(cryo)
temperature.
For
alone,
room-temperature
(RT)
crystallography
can
reveal
previously
hidden,
biologically
relevant
alternate
conformations.
However,
less
is
understood
about
RT
may
impact
the
conformational
landscapes
protein-ligand
complexes.
Previously,
we
showed
that
fragments
cluster
in
putative
allosteric
sites
using
a
cryo
crystallographic
screen
therapeutic
target
PTP1B
(Keedy
et
al.,
2018).
Here,
have
performed
two
screens
many
same
fragments,
representing
largest
diverse
library
to
date,
and
enabling
direct
interrogation
effect
data
collection
temperature
on
interactions.
We
show
RT,
fewer
bind,
often
more
weakly
–
but
variety
temperature-dependent
differences,
including
unique
binding
poses,
changes
solvation,
new
sites,
distinct
protein
responses.
Overall,
this
work
suggests
vast
body
existing
cryo-temperature
provide
an
incomplete
picture,
highlights
potential
help
complete
picture
by
revealing
modes
systems.
Our
results
inspire
future
use
interrogate
roles
ensembles
biological
function.
Bioorganic & Medicinal Chemistry Letters,
Journal Year:
2013,
Volume and Issue:
24(1), P. 33 - 39
Published: Oct. 10, 2013
In
recent
years,
the
number
of
drug
candidates
with
a
covalent
mechanism
action
progressing
through
clinical
trials
or
being
approved
by
FDA
has
increased
significantly.
And
as
interest
in
inhibitors
increased,
technical
challenges
for
characterizing
and
optimizing
these
have
become
evident.
A
new
tools
been
developed
to
aid
this
process,
but
not
gained
wide-spread
use.
This
review
will
highlight
methods
useful
prosecuting
inhibitor
discovery
programs.
Journal of Medicinal Chemistry,
Journal Year:
2014,
Volume and Issue:
57(11), P. 4969 - 4974
Published: May 28, 2014
A
novel
fragment-based
drug
discovery
approach
is
reported
which
irreversibly
tethers
drug-like
fragments
to
catalytic
cysteines.
We
attached
an
electrophile
100
without
significant
alterations
in
the
reactivity
of
electrophile.
mass
spectrometry
assay
discovered
three
nonpeptidic
inhibitors
cysteine
protease
papain.
The
identified
compounds
display
characteristics
irreversible
inhibitors.
tethering
system
also
displays
specificity:
papain
did
not
covalently
react
with
UbcH7,
USP08,
or
GST-tagged
human
rhinovirus
3C
protease.
Essays in Biochemistry,
Journal Year:
2017,
Volume and Issue:
61(5), P. 453 - 464
Published: Nov. 8, 2017
It
is
over
20
years
since
the
first
fragment-based
discovery
projects
were
disclosed.
The
methods
are
now
mature
for
most
‘conventional’
targets
in
drug
such
as
enzymes
(kinases
and
proteases)
but
there
has
also
been
growing
success
on
more
challenging
targets,
disruption
of
protein–protein
interactions.
main
application
to
identify
tractable
chemical
startpoints
that
non-covalently
modulate
activity
a
biological
molecule.
In
this
essay,
we
overview
current
practice
discuss
how
they
have
had
an
impact
lead
–
generating
large
number
fragment-derived
compounds
clinical
trials
two
medicines
treating
patients.
addition,
some
recent
applications
biology
providing
tools
investigate
molecules,
mechanisms
systems.