Journal of Enzyme Inhibition and Medicinal Chemistry,
Journal Year:
2023,
Volume and Issue:
38(1)
Published: Nov. 13, 2023
Alzheimer's
disease
(AD)
is
a
progressive
brain
characterised
by
memory
loss
and
cognition
impairment,
ultimately
leading
to
death.
There
are
three
FDA-approved
acetylcholinesterase
inhibitors
(donepezil,
rivastigmine,
galantamine,
AChEIs)
for
the
symptomatic
treatment
of
AD.
Monoamine
oxidase
B
(MAO-B)
has
been
considered
contribute
pathologies
Therefore,
we
reviewed
dual
(AChE)
MAO-B
developed
in
last
five
years.
In
this
review,
these
dual-target
were
classified
into
six
groups
according
basic
parent
structure,
including
chalcone,
coumarin,
chromone,
benzo-fused
five-membered
ring,
imine
hydrazine,
other
scaffolds.
Their
design
strategies,
structure-activity
relationships
(SARs),
molecular
docking
studies
with
AChE
analysed
discussed,
giving
valuable
insights
subsequent
development
inhibitors.
Challenges
balanced
potent
noted,
corresponding
solutions
provided.
Journal of Biochemical and Molecular Toxicology,
Journal Year:
2024,
Volume and Issue:
38(1)
Published: Jan. 1, 2024
Abstract
Isonicotinohydrazide
is
the
first‐line
medication
in
prevention
and
treatment
of
tuberculosis.
Antitubercular,
antibacterial,
antifungal,
antiviral,
anti‐inflammatory,
antimalarial
activity,
anticancer,
antineoplastic
anti‐HIV
activity
are
all
demonstrated
by
drugs
with
a
pyrimidine
ring.
The
current
study
focuses
on
synthesis
N‐(4‐(substituted‐phenyl)‐6‐(substituted‐aryl)
pyrimidin‐2‐yl)‐2‐(2‐isonicotinoylhydrazinyl)
acetamide
from
isonicotinohydrazide.
Newly
synthesized
compounds
were
characterized
spectral
studies
(IR,
1
H‐NMR,
13
C‐NMR,
mass
spectroscopy).
They
screened
for
their
antituberculosis,
antimalarial,
antiprotozoal
activities
compared
standard
drugs.
Molecular
docking
isonicotinohydrazide‐bearing
motifs
was
also
done
some
active
compounds.
Journal of Biomolecular Structure and Dynamics,
Journal Year:
2024,
Volume and Issue:
unknown, P. 1 - 19
Published: Feb. 2, 2024
In
this
study,
a
comprehensive
investigation
of
set
phytochemicals
to
identify
potential
inhibitors
for
the
Forkhead
box
protein
M1
(FOXM1)
was
conducted.
FOXM1
is
overexpressed
in
glioblastoma
(GBM)
cells
and
plays
crucial
role
cell
cycle
progression,
proliferation,
invasion.
have
shown
promising
results
preclinical
studies,
ongoing
clinical
trials
are
assessing
their
efficacy
GBM
patients.
However,
there
limited
studies
on
identification
novel
compounds
against
attractive
therapeutic
target.
To
address
this,
NPACT
database
containing
1,574
used,
employing
hierarchical
multistep
docking
approach,
followed
by
an
estimation
relative
binding
free
energy.
By
fixing
user-defined
XP-dock
MM-GBSA
cut-off
scores
−6.096
−37.881
kcal/mol,
chemical
space
further
narrowed.
Through
exhaustive
analysis
molecular
interactions
various
pharmacokinetics
profiles,
we
identified
four
compounds,
namely
NPACT00002,
NPACT01454,
NPACT00856,
NPACT01417,
as
inhibitors.
assess
stability
protein-ligand
dynamic
conditions,
100
ns
Molecular
dynamics
(MD)
simulations
were
performed.
Furthermore,
mechanics
with
generalized
Born
surface
area
solvation
(MM-GBSA)
based
energy
estimations
entire
simulation
trajectories
revealed
strong
affinity
all
towards
FOXM1,
surpassing
that
control
drug
Troglitazone.
Based
extensively
studied
approaches,
propose
these
molecules
hold
promise
applications
GBM.
experimental
validation
will
be
necessary
confirm
targeted
therapies.
Journal of Cellular Biochemistry,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Sept. 19, 2024
ABSTRACT
This
study
investigates
the
repurposing
potential
of
non‐nucleosidic
reverse
transcriptase
inhibitors
(NNRTIs),
specifically
Rilpivirine
and
Etravirine,
as
L858R/T790M
tyrosine
kinase
for
addressing
acquired
resistance
in
non‐small
cell
lung
cancer
(NSCLC).
Using
silico
molecular
docking,
demonstrated
a
docking
score
−7.534
kcal/mol,
comparable
to
established
epidermal
growth
factor
receptor
(EGFR
TKIs)
like
Osimertinib
WZ4002.
Molecular
dynamics
(MD)
simulations
over
200
ns
revealed
stability
Rilpivirine–EGFR
complex,
with
RMSD
values
ranging
from
2.5
3.5
Å.
The
vitro
antiproliferative
assays
showed
that
had
an
IC
50
value
2.3
µM
against
H1975
cells,
while
WZ4002
0.291
µM,
indicating
moderate
efficacy.
Enzymatic
inhibited
double
mutant
TK)
54.22
nM
spared
wild‐type
EGFR
TK
22.52
nM.
These
findings
suggest
Rilpivirine's
therapeutic
agent
NSCLC
mutations
Journal of Biomolecular Structure and Dynamics,
Journal Year:
2024,
Volume and Issue:
unknown, P. 1 - 19
Published: Oct. 15, 2024
The
enzyme
Asparaginyl
Endopeptidase
(AEP)
is
associated
with
proteinopathy-related
pathologies
such
as
Alzheimer's
disease
(AD)
and
Frontal
Temporal
Dementia
(FTD).
onset
of
by
AEP
due
to
cleaved
fragments
forming
protein
aggregates
resulting
in
neurodegeneration.
Unfortunately,
there
are
no
clinically
approved
small
molecule
inhibitors
for
AEP,
therefore,
it
serves
an
unmet
medical
need
the
design
development
potential
novel
molecules.
In
developing
proteolytic
activity,
a
structured
approach
utilizing
structure-based
computer-aided
drug
(SB-CADD)
parameters
was
employed.
This
involved
virtual
high
throughput
screening
(vHTS)
across
various
CNS-focused
databases
enriched
diverse
functionality.
We
identified
top
sixty
ligands
based
on
glide
XP-docking
score
out
10
million
ligands.
free
binding
energy
then
calculated
using
MM-GBSA
all
selected
molecules
which
resulted
discovering
that
AEPI-1
AEPI-6
(Asparaginyl
inhibitors)
displayed
affinity
towards
catalytic
triad.
Further
investigation
determined
six
hits
form
stable
complexes
during
50
ns
molecular
dynamic
simulations.
also
observed
AEPI-2
demonstrated
highest
stability
within
pockets.
Post-MD
analyses
DCCM,
PCA,
PDF,
ADMET
properties
were
evaluated.
By
bridging
observations,
we
these
occupy
active
site
β-helix
(β1,
β3,
β4)
S1
pocket
additional
sites
α1
β5,
suggesting
its
suitability
candidate
discovery
against
Endopeptidase.
Chemistry & Biodiversity,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Oct. 29, 2024
This
study
explores
the
therapeutic
potential
of
three
proaporphine
alkaloids-cissamaline,
cissamanine,
and
cissamdine,
which
were
recently
isolated
from
Cissampelos
capensis
L.f.,
against
Parkinson's
disease
(PD).
Using
computational
techniques,
we
investigated
their
efficacy
as
inhibitors
a
key
protein
in
PD.
ADMET
analysis
demonstrated
that
these
alkaloids
conform
to
Lipinski,
Pfizer,
Golden
Triangle,
GSK
rules,
indicating
favorable
safety,
oral
bioavailability,
high
probability
passing
human
intestinal
blood-brain
barriers.
They
neither
substrates
nor
any
CYP
enzymes
tested,
minimal
metabolic
interference
an
enhanced
safety
profile.
Molecular
docking
studies
revealed
binding
energies
-9.05
kcal/mol
(cissamaline),
-9.95
(cissamanine),
-10.65
(cissamdine)
MAO-B,
critical
PD
target,
surpassing
control
(zonisamide,
-6.96
kcal/mol).
The
molecular
interaction
analyses
also
promising,
with
interactions
comparable
control.
dynamics
(MD)
simulations
confirmed
stable
protein-ligand
interactions,
root-mean-square
deviation
(RMSD)
values
ranging
1.03
Å
3.92
Å,
fluctuation
(RMSF)
remaining
below
1.14
radius
gyration
(RGyr)
between
20.20
20.50
compact
structures.
Hydrogen
bonding
maximum
hydrogen
bond
counts
6
5
4
(cissamdine),
demonstrating
robust
MAO-B.
Density
Functional
Theory
(DFT)
calculations
highest
electrophilicity
(ω
=0.151),
electron
affinity
(EA
=0.075),
smallest
HOMO-LUMO
gap
(ΔE
=0.130)
for
reactivity.
These
results
advocate
further
vitro
vivo
evaluate
compounds'
therapeutics.
