International Journal of Molecular Sciences,
Год журнала:
2025,
Номер
26(8), С. 3781 - 3781
Опубликована: Апрель 17, 2025
Acetylcholinesterase
(AChE)
is
a
critical
enzyme
involved
in
neurotransmission
by
hydrolyzing
acetylcholine
at
the
synaptic
cleft,
making
it
key
target
for
drug
discovery,
particularly
treatment
of
neurodegenerative
disorders
such
as
Alzheimer’s
disease.
Computational
approaches,
molecular
docking
and
dynamics
(MD)
simulations,
have
become
indispensable
tools
identifying
optimizing
AChE
inhibitors
predicting
ligand-binding
affinities,
interaction
mechanisms,
conformational
dynamics.
This
review
serves
comprehensive
guide
future
research
on
using
MD
simulations.
It
compiles
analyzes
studies
conducted
over
past
five
years,
providing
evaluation
most
widely
used
computational
tools,
including
AutoDock,
AutoDock
Vina,
GROMACS,
which
significantly
contributed
to
advancement
inhibitor
screening.
Furthermore,
we
identify
PDB
ID:
4EY7,
frequently
crystal
structure
studies,
highlight
Donepezil,
well-established
reference
molecule
employed
control
screening
novel
inhibitors.
By
examining
these
aspects,
this
aims
enhance
accuracy
reliability
virtual
approaches
researchers
selecting
appropriate
methodologies.
The
integration
simulations
not
only
improves
hit
identification
lead
optimization
but
also
provides
deeper
mechanistic
insights
into
AChE–ligand
interactions,
contributing
rational
design
more
effective
Abstract
Polyol
pathway
enzymes,
aldose
reductase
(EC
1.1.1.21;
AR,
ALR2),
and
sorbitol
dehydrogenase
1.1.1.14;
SDH,
SORD)
have
been
widely
investigated
as
the
enzymes
crucially
involved
in
pathogenesis
of
several
chronic
complications,
including
nephropathy,
neuropathy,
retinopathy,
cataracts
associated
with
diabetes
mellitus.
Although
phenolic
compounds
reported
to
possess
many
other
biological
activities,
continuation
our
interest
designing
discovering
potent
inhibitors
AR
herein,
we
evaluated
these
agents’
inhibitory
potential
against
polyol
enzymes.
Our
vitro
studies
revealed
that
all
derivatives
show
activity
recombinant
human
(r
h
AR)
SDH
SDH),
K
I
constants
ranging
from
9.37±0.16
μM
77.22±2.49
2.51±0.10
42.16±1.03
μM,
respectively.
Among
agents,
Prunetin
Phloridzin
showed
prominent
versus
r
while
some
were
also
determined
perfect
dual
activity.
Moreover,
silico
performed
rationalize
binding
site
interactions
agents
target
enzyme
SDH.
According
ADME‐Tox
was
be
exhibiting
suitable
drug‐like
properties.
The
identified
therapeutic
potentials
this
study
may
promising
for
developing
lead
prevent
complications.
Archiv der Pharmazie,
Год журнала:
2023,
Номер
356(4)
Опубликована: Янв. 5, 2023
In
the
search
for
small-molecule
aldose
reductase
(AR)
inhibitors,
new
tetrazole-hydrazone
hybrids
(1-15)
were
designed.
An
efficient
procedure
was
employed
synthesis
of
compounds
1-15.
All
hydrazones
subjected
to
an
in
vitro
assay
assess
their
AR
inhibitory
profiles.
Compounds
1-15
caused
inhibition
with
Ki
values
ranging
between
0.177
and
6.322
µM
IC50
0.210
0.676
µM.
2-[(1-(4-Hydroxyphenyl)-1H-tetrazol-5-yl)thio]-N'-(4-fluorobenzylidene)acetohydrazide
(4)
most
potent
inhibitor
this
series.
Compound
4
markedly
inhibited
(IC50
=
0.297
µM)
a
competitive
manner
(Ki
compared
epalrestat
0.857
µM,
0.267
µM).
Based
on
data
obtained
by
applying
MTT
test,
compound
showed
no
cytotoxic
activity
toward
normal
(NIH/3T3)
cells
at
tested
concentrations,
indicating
its
safety
as
inhibitor.
exhibited
proper
interactions
crucial
amino
acid
residues
within
active
site
AR.
silico
QikProp
all
also
determined
pharmacokinetic
Taken
together,
stands
out
promising
further
vivo
studies.
Journal of Biomolecular Structure and Dynamics,
Год журнала:
2024,
Номер
unknown, С. 1 - 19
Опубликована: Март 27, 2024
Various
carbonic
anhydrase
(CA)
enzyme
isoforms
are
known
today.
In
addition
to
the
use
of
CA
inhibitors
as
diuretics,
antiepileptics
and
antiglaucoma
agents,
inhibition
other
specific
was
reported
have
clinical
benefits
in
cancers.
this
study,
two
groups
1,3,4-thiadiazole
derivatives
were
designed
synthesized
act
human
I
II
(hCA
hCA
II)
inhibitors.
The
activities
these
compounds
tested
vitro
evaluated
silico
studies.
activity
also
against
acetylcholinesterase
(AChE)
evaluate
relation
newly
structures
AChE.
analyzed
by
1H
NMR,13C
NMR
high-resolution
mass
spectroscopy
(HRMS).
results
displayed
a
better
all
than
that
commonly
used
standard
drug,
Acetazolamide
(AAZ).
showed
II,
except
for
5b
6b.
Only
6a
6c
superior
AChE
compared
agent,
tacrine
(THA).
studies,
including
absorption,
distribution,
metabolism
excretion
(ADME)
drug-likeness
evaluation,
molecular
docking,
dynamic
simulations
(MDSs)
density
functional
theory
(DFT)
calculations,
compatible
with
presented
details
regarding
structure–activity
relationship.
Journal of Enzyme Inhibition and Medicinal Chemistry,
Год журнала:
2023,
Номер
38(1)
Опубликована: Март 2, 2023
A
novel
series
of
twelve
aromatic
bis-ureido-substituted
benzenesulfonamides
was
synthesised
by
conjugation
aminobenzenesulfonamides
with
bis-isocyanates.
The
obtained
derivatives
were
tested
against
four
selected
human
carbonic
anhydrase
isoforms
(hCA
I,
hCA
II,
IX
and
XII).
Most
the
new
compounds
showed
an
effective
inhibitory
profile
XII,
also
having
some
selectivity
respect
to
I
II.
inhibition
constants
these
XII
in
range
6.73-835
5.02-429
nM,
respectively.
Since
are
important
drug
targets
for
anti-cancer/anti-metastatic
drugs,
inhibitors
reported
here
may
be
considered
interest
cancer
related
studies
which
enzymes
involved.
Journal of Biomolecular Structure and Dynamics,
Год журнала:
2023,
Номер
42(9), С. 4710 - 4729
Опубликована: Июнь 22, 2023
A
series
of
novel
benzimidazole-derived
carbohydrazones
was
designed,
synthesized
and
evaluated
for
their
dual
inhibition
potential
against
monoamine
oxidases
(MAOs)
acetylcholinesterase
(AChE)
using
multitarget-directed
ligand
approach
(MTDL).
The
investigated
compounds
have
exhibited
moderate
to
excellent
Chemistry & Biodiversity,
Год журнала:
2023,
Номер
21(2)
Опубликована: Дек. 27, 2023
The
present
study
focused
on
the
synthesis
and
characterization
of
novel
pyrazole
carboxamide
derivatives
(SA1-12).
inhibitory
effect
compounds
cholinesterases
(ChEs;
AChE
BChE)
carbonic
anhydrases
(hCAs;
hCA
I
II)
isoenzymes
were
screened
as
in
vitro.
These
series
have
been
identified
potential
inhibitors
with
a
K
This
study
introduces
a
series
of
ten
hybrid
molecules
DK(1-10),
which
combine
diazo
and
coumarin
moieties
along
with
diverse
aromatic
substitutions.
The
primary
objective
was
to
evaluate
the
inhibitory
capabilities
these
compounds
against
four
prominent
isoforms:
cytosolic
hCA
I
II,
as
well
tumor-associated
membrane-bound
IX
XII.
Impressively,
majority
tested
exhibited
significant
inhibition
activity
isoforms
XII,
K
