The
search
for
acetylcholinesterase
(AChE)
inhibitors
produced
by
natural
sources
is
of
great
significance
the
prevention
and
therapy
Alzheimer's
disease
has
been
widely
concerned.
In
this
study,
fisetin,
a
flavonoid
compound
plant
origin,
displayed
mixed
inhibition
mode
on
AChE
(IC50
=
8.88
±
0.14
μM).
Fluorescence
spectra
analysis
revealed
that
fisetin
statically
quenched
fluorescence,
ground
state
complex
was
formed
hydrogen
bonds
hydrophobic
interactions.
Circular
dichroism
assays
showed
induced
structure
loosened
with
decrease
in
α-helix
structure.
Computer
simulation
exhibited
bound
to
both
peripheral
anionic
site
(PAS)
catalytic
active
(CAS)
increased
stability
AChE.
Interestingly,
combination
galantamine
enhanced
binding
affinity
between
further
loosened,
while
still
type.
heatmap
indicated
(0.2
μM)
combined
(2.25
had
significant
synergy
inhibition,
probably
because
at
PAS-AChE
conformation
changes
gorge
CAS,
which
loose
mixture,
so
finally
interaction
substrate
strongly
affected.
This
work
may
offer
theoretical
reference
functional
research
as
potential
inhibitor
an
supplement
galantamine.
Foods,
Год журнала:
2023,
Номер
12(4), С. 905 - 905
Опубликована: Фев. 20, 2023
The
inhibitory
activity
of
hesperetin
on
polyphenol
oxidase
(PPO)
and
their
interaction
characteristics
were
investigated
using
multiple
spectroscopic
methods
computational
simulation.
Hesperetin,
a
mixed
inhibitor,
reversibly
inhibited
PPO
activity,
its
half-maximum
concentration
(IC50)
values
monophenolase
diphenolase
80.8
±
1.4
μM
776.0
15.5
μM,
respectively.
Multivariate
curve
resolution-alternate
least
squares
(MCR-ALS)
analysis
suggested
interacted
with
formed
PPO-hesperetin
complex.
Hesperetin
statically
quenched
PPO's
endogenous
fluorescence,
hydrophobic
interactions
mainly
drove
binding.
affected
the
polarity
microenvironment
around
Trp
residues
in
PPO,
but
had
no
effect
that
Tyr
residues.
Circular
dichroism
(CD)
results
showed
increased
α-helix
content
decreased
β-fold
random
coil
contents,
thus
tightening
structure.
Molecular
docking
entered
cavity
bound
near
dinuclear
copper
active
center,
Val283,
Phe264,
His85,
Asn260,
Val248,
His263
via
interactions,
hydrogen
bonds
Met280,
His89,
His259
also
Phe292,
His61,
Phe90,
Glu256,
His244,
Gly281
van
der
Waals
forces.
molecular
dynamics
simulation
demonstrated
addition
reduced
stability
hydrophobicity
structural
denseness.
Thus,
inhibition
may
be
because
center
surrounding
residues,
occupied
binding
site
for
substrate,
induced
changes
secondary
structure,
inhibiting
catalytic
PPO.
This
study
provide
novel
views
theoretical
guidance
developing
flavonoids
as
new
efficient
inhibitors.
International Journal of Molecular Sciences,
Год журнала:
2023,
Номер
24(6), С. 5216 - 5216
Опубликована: Март 9, 2023
Cancer
represents
the
main
cause
of
morbidity
and
mortality
worldwide,
constituting
a
serious
health
problem.
In
this
context,
melanoma
most
aggressive
fatal
type
skin
cancer,
with
death
rates
increasing
every
year.
Scientific
efforts
have
been
addressed
to
development
inhibitors
targeting
tyrosinase
enzyme
as
potential
anti-melanoma
agents
due
importance
in
melanogenesis
biosynthesis.
Coumarin-based
compounds
shown
activity
inhibitors.
study,
coumarin-based
derivatives
were
designed,
synthesized,
experimentally
evaluated
upon
tyrosinase.
Compound
FN-19,
coumarin-thiosemicarbazone
analog,
exhibited
potent
anti-tyrosinase
activity,
an
IC50
value
42.16
±
5.16
µM,
being
more
active
than
ascorbic
acid
kojic
acid,
both
reference
The
kinetic
study
showed
that
FN-19
acts
mixed
inhibitor.
Still,
for
compound,
molecular
dynamics
(MD)
simulations
performed
determine
stability
complex
tyrosinase,
generating
RMSD,
RMSF,
interaction
plots.
Additionally,
docking
studies
elucidate
binding
pose
at
suggesting
hydroxyl
group
coumarin
derivative
performs
coordinate
bonds
(bidentate)
copper(II)
ions
distances
ranging
from
2.09
2.61
Å.
Then,
MM/PBSA
calculations
revealed
van
der
Waals
interactions
are
relevant
intermolecular
forces
stabilization.
Furthermore,
it
was
observed
has
energy
(ΔEMM)
similar
tropolone,
Therefore,
data
obtained
will
be
useful
designing
developing
novel
analogs
enzyme.
