Pharmacophore-based virtual screening and in silico investigations of small molecule library for discovery of human hepatic ketohexokinase inhibitors for the treatment of fructose metabolic disorders
Frontiers in Pharmacology,
Год журнала:
2025,
Номер
16
Опубликована: Апрель 7, 2025
Excessive
fructose
consumption
is
a
significant
driver
of
metabolic
disorders,
including
obesity,
diabetes,
non-alcoholic
fatty
liver
disease
and
steatohepatitis
primarily
by
promoting
insulin
resistance
fat
accumulation.
Ketohexokinase
C
(KHK-C),
pivotal
enzyme
in
metabolism,
catalyzes
the
phosphorylation
to
fructose-1-phosphate,
initiating
cascade
downstream
processes.
In
contrast
glucose
KHK-C
lacks
negative
feedback
regulation,
allowing
continuous
fructose,
which
leads
heightened
levels
glucose,
glycogen,
triglycerides
bloodstream
liver.
While
targeting
offers
promising
therapeutic
avenue,
no
drugs
have
yet
been
approved
for
clinical
use.
Pfizer's
PF-06835919
has
progressed
phase
II
trials,
demonstrating
reduction
improved
sensitivity,
while
Eli
Lilly's
LY-3522348
also
shows
potential.
Nonetheless,
there
remains
critical
need
development
novel
inhibitors
that
offer
pharmacokinetics,
enhanced
efficacy,
superior
safety
profiles.
present
study,
comprehensive
computational
strategy
was
employed
screen
460,000
compounds
from
National
Cancer
Institute
library
potential
inhibitors.
Initially,
pharmacophore-based
virtual
screening
used
identify
hits,
followed
multi-level
molecular
docking,
binding
free
energy
estimation,
pharmacokinetic
analysis,
dynamics
(MD)
simulations
further
evaluate
compounds.
This
multi-step
approach
aimed
with
strong
affinity,
favorable
profiles,
high
efficacy
as
Ten
exhibited
docking
scores
ranging
-7.79
-9.10
kcal/mol,
surpassing
those
currently
undergoing
(-7.768
kcal/mol)
(-6.54
kcal/mol).
Their
calculated
energies
ranged
-57.06
-70.69
their
superiority
over
(-56.71
(-45.15
ADMET
profiling
refined
selection
five
(1,
2,
4-6),
identified
compound
2
most
stable
candidate
compared
PF-06835919.
These
findings
highlight
potent
inhibitor
predicted
pharmacokinetics
toxicity
profiles
supporting
its
treating
fructose-driven
warranting
validation.
Язык: Английский
Identification of Microbial-Based Natural Products as Potential CYP51 Inhibitors for Eumycetoma Treatment: Insights from Molecular Docking, MM-GBSA Calculations, ADMET Analysis, and Molecular Dynamics Simulations
Pharmaceuticals,
Год журнала:
2025,
Номер
18(4), С. 598 - 598
Опубликована: Апрель 20, 2025
Background/Objectives:
Eumycetoma,
caused
by
Madurella
mycetomatis,
is
a
chronic
fungal
infection
with
limited
treatment
options
and
increasing
drug
resistance.
CYP51,
key
enzyme
in
ergosterol
biosynthesis,
well-established
target
for
azole
antifungals.
However,
existing
drugs
demonstrate
efficacy
treating
eumycetoma.
Microbial-based
natural
products,
their
structural
diversity
bioactivity,
offer
promising
source
novel
CYP51
inhibitors.
This
study
aimed
to
identify
potential
mycetomatis
inhibitors
from
microbial
products
using
molecular
docking,
MM-GBSA
calculations,
ADMET
analysis,
dynamics
(MD)
simulations.
Methods:
Virtual
screening
was
conducted
on
library
of
microbial-based
an
in-house
homology
model
itraconazole
as
the
reference
drug.
The
top
compounds
initial
docking
were
refined
through
Standard
Extra
Precision
docking.
calculations
assessed
binding
affinities,
analysis
evaluated
drug-like
properties.
Compounds
favorable
properties
underwent
MD
Results:
computational
investigations
identified
34
better
scores
affinity
than
itraconazole.
Of
these,
9
interacted
heme
group
residues
active
site
CYP51.
In
silico
pharmacokinetic
profiling
3
candidates,
simulations
confirmed
Conclusions:
highlights
microbial-derived
particularly
monacyclinone
G,
H,
I,
candidates
inhibition,
eumycetoma,
requiring
further
experimental
validation.
Язык: Английский