Enhancing HDAC Inhibitor Screening: Addressing Zinc Parameterization and Ligand Protonation in Docking Studies
International Journal of Molecular Sciences,
Год журнала:
2025,
Номер
26(2), С. 850 - 850
Опубликована: Янв. 20, 2025
Precise
binding
free-energy
predictions
for
ligands
targeting
metalloproteins,
especially
zinc-containing
histone
deacetylase
(HDAC)
enzymes,
require
specialized
computational
approaches
due
to
the
unique
interactions
at
metal-binding
sites.
This
study
evaluates
a
docking
algorithm
optimized
zinc
coordination
determine
whether
it
could
accurately
differentiate
between
protonated
and
deprotonated
states
of
hydroxamic
acid
ligands,
key
functional
group
in
HDAC
inhibitors
(HDACi).
By
systematically
analyzing
both
protonation
states,
we
sought
identify
which
state
produces
poses
energy
estimates
most
closely
aligned
with
experimental
values.
The
was
applied
across
2,
4,
8,
comparing
ligand
correlations
data.
results
demonstrate
that
consistently
yielded
stronger
data,
R2
values
outperforming
counterparts
all
targets
(average
=
0.80
compared
form
where
0.67).
These
findings
emphasize
significance
proper
molecular
studies
zinc-binding
particularly
HDACs,
suggest
deprotonation
enhances
predictive
accuracy.
study’s
methodology
provides
robust
foundation
improved
virtual
screening
protocols
evaluate
large
libraries
efficiently.
approach
supports
streamlined
discovery
high-affinity,
HDACi,
advancing
therapeutic
exploration
metalloprotein
targets.
A
comprehensive,
step-by-step
tutorial
is
provided
facilitate
thorough
understanding
enable
reproducibility
results.
Язык: Английский
HDAC6 mediates tumorigenesis during mitosis and the development of targeted deactivating agents
Bioorganic Chemistry,
Год журнала:
2024,
Номер
153, С. 107818 - 107818
Опубликована: Сен. 10, 2024
Язык: Английский
Deciphering the Therapeutic Potential of Novel Pentyloxyamide-Based Class I, IIb HDAC Inhibitors against Therapy-Resistant Leukemia
Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 27, 2024
Histone
deacetylase
inhibitors
(HDACi)
are
established
anticancer
drugs,
especially
in
hematological
cancers.
This
study
aimed
to
design,
synthesize,
and
evaluate
a
set
of
HDACi
featuring
pentyloxyamide
connecting
unit
linker
region
substituted
phenylthiazole
cap
groups.
A
structural
optimization
program
yielded
with
nanomolar
inhibitory
activity
against
histone
class
I/IIb
enzymes.
The
novel
(
Язык: Английский