Computer-aided drug design of novel nirmatrelvir analogs inhibiting main protease of Coronavirus SARS-CoV-2
Journal of Applied Pharmaceutical Science,
Год журнала:
2024,
Номер
unknown
Опубликована: Янв. 1, 2024
A
computer-aided
drug
design
of
new
derivatives
nirmatrelvir,
an
orally
active
inhibitor
the
main-protease
(Mpro)
severe
acute
respiratory
syndrome
Coronavirus
2
(SARS-CoV-2),
was
performed
to
identify
its
analogues
with
a
higher
antiviral
potency.
The
following
workflow
used:
first,
evolutionary
library
composed
1,866
generated
starting
from
parent
nirmatrelvir
scaffold
and
going
through
small
mutation,
fitness
scoring,
ranking,
selection.
Second,
preprocessed
filtered
against
3-D
pharmacophore
model
built
X-ray
structure
in
co-crystalized
complex
Mpro
enzyme,
allowing
us
reduce
chemical
space
32
analogues.
Third,
structure-based
molecular
docking
two
different
enzyme
structures
further
ranked
these
candidates,
so
that
up
eight
better-binding
analogs
were
identified.
selected
hit-analogues
target
enzymes
SARS-CoV-2
binding
affinity
than
nirmatrelvir.
main
structural
modifications
increase
overall
inhibitory
are
identified
at
azabicyclo[3.1.0]
hexane
2-oxopyrrolidine
fragments.
characteristic
feature
centre
is
similar
location
trifluoroacetylamino
fragment,
which
observed
for
most
hit-analogues.
suggested
rational
noncovalent
inhibitors
based
on
approved
drugs
promising,
extremely
low-cost,
time-efficient
approach
development
potential
pharmaceutical
ingredients
treatment
Disease
2019.
Язык: Английский
Critical assessment of popular biomolecular force fields for molecular dynamics simulations of folding and enzymatic activity of main protease of coronavirus SARS-CoV-2
Biophysical Chemistry,
Год журнала:
2024,
Номер
311, С. 107258 - 107258
Опубликована: Май 16, 2024
Язык: Английский
Recent advances in computational drug discovery for therapy against coronavirus SARS-CoV-2
ScienceRise Pharmaceutical Science,
Год журнала:
2023,
Номер
6(46)
Опубликована: Дек. 31, 2023
Despite
essential
experimental
efforts
focused
on
studying
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2),
computational
chemistry
methods
are
promising
complementary
tools
in
combating
disease
2019
(COVID-19).
The
present
review
aims
to
provide
readers
with
the
recent
progress
and
advances
approaches
currently
used
streamline
drug
discovery
development
context
of
COVID-19.
Our
is
dual
purpose.
It
intended
(a)
familiarize
readership
general
concept
QSAR,
silico
screening,
molecular
docking
dynamics
(MD)
simulations
(b)
key
examples
applications
these
discovering
novel
therapeutic
agents
against
We
outline
how
structure-
ligand-based
design
can
accelerate
structural
elucidation
pharmacological
targeting
preclinical
candidate
molecules.
Several
MD
studies
demonstrate
atomistic
facilitate
our
understanding
basis
actions
biological
mechanisms
virus
inhibition
atomic
detail.
Finally,
short-
long-term
perspectives
discussed.
aim
this
study
summarize
last
three
years'
process
Materials
methods.
literature
overview
machine
learning,
given
search
was
performed
using
online
databases,
such
as
Scopus,
Web
Science,
PDB-protein
databank,
PubMed,
focusing
following
keywords
-
human
coronavirus,
docking,
virtual
dynamics,
Mpro
PLpro
proteases,
SARS-CоV-2,
respectively.
Results.
familiarizes
provides
Conclusions.
New
insight
into
achievements
computer-guided
for
SARS-CoV-2
provided
Язык: Английский
Computer-aided rational design and synthesis of new potential antihypertensive agents among 1,2,3-triazole-containing nifedipine analogs
ScienceRise Pharmaceutical Science,
Год журнала:
2024,
Номер
3 (49), С. 4 - 12
Опубликована: Июнь 30, 2024
1,2,3-Triazole-containing
Nifedipine
analogues
offer
the
opportunity
to
increase
biostability,
bioavailability,
efficacy
and
binding
selectivity
target
receptors.
Here,
we
applied
a
computer-aided
rational
design
for
identifying
new
containing
1,2,3-triazole
moiety.
First,
chemical
library
of
796
derivatives
combining
DHP
fragment
moiety
was
generated.
Second,
reduce
size,
pre-filtered
using
two
3D-pharmacophore
models
with
different
complexity,
which
allowed
us
gradually
space,
ending
up
26
hit
candidates.
Molecular
docking
calculations
against
rCav1.1
receptor
identification
eight
5a-h,
characterized
by
affinity
towards
same
level
as
approved
Nifedipine-like
drugs.
Next,
our
molecular
results
were
used
guide
optimize
retrosynthetic
approaches
promising
antihypertensive
agents.
So,
approach
ring
in
position
4
proposed.
Finally,
5a-h
determined
synthesized
suggested
approach.
The
aim
this
study
is
identify
drug
Materials
Methods.
organic
synthesis
Computer-aided
pharmacophore
screening
calculations.
Results.
made
it
possible
estimate
receptor.
Pharmacophore
analogues,
consisting
derivatives,
reducing
space
obtaining
candidates
high
Using
method
docking,
hits
identified,
recommended
compounds
proposed
performed.
Conclusions.
showed
that
are
at
indicate
key
features
ligand-receptor
interaction
can
A
proposed,
Язык: Английский
Interaction of some chalcone derivatives with calcium channels using a theoretical model
Brazilian Journal of Science,
Год журнала:
2024,
Номер
3(11), С. 1 - 15
Опубликована: Окт. 10, 2024
For
several
years,
different
drugs
have
been
used
to
treat
heart
failure,
such
as
digoxin,
captopril,
spironolactone,
milrinone,
levosimedam,
dobutamine,
and
others.
However,
some
of
these
can
produce
secondary
effects
arrhythmia,
cough,
hyperkalemia,
Analyzing
data,
this
study
aimed
evaluate
the
interaction
chalcone
derivatives
(1-17)
with
calcium
channels
using
theoretical
models.
It
is
important
mention
that
7pjx
protein,
nifedipine,
amlodipine,
diltiazem,
verapamil
were
tools
in
DockingServer
program.
The
results
showed
differences
compared
drugs.
Other
data
indicate
inhibition
constant
(Ki)
for
analog
1
was
lower
verapamil,
diltiazem.
Besides,
other
suggest
Ki
compound
11
All
could
act
channel
inhibitors;
phenomenon
be
translated
into
changes
blood
pressure
through
a
decrease
intracellular
levels.
These
good
therapeutic
alternatives
failure.
Язык: Английский
Towards the discovery of molecules with anti-COVID-19 activity: Relationships between screening and docking results
Kharkov University Bulletin Chemical Series,
Год журнала:
2024,
Номер
42, С. 6 - 14
Опубликована: Июнь 21, 2024
The
study
presents
the
results
of
a
combined
approach
to
theoretical
description
potential
antiviral
activity
against
COVID-19.
We
found
that
pharmacophore
screening
based
on
limited
experimental
data
"protein-ligand"
binding
complexes
might
have
low
predictive
ability.
Therefore,
in
this
study,
we
build
model
statistical
QSAR
for
obtained
from
docking
which
serves
as
basis
adequate
prediction
ligand
activity.
use
logistic
regression
construct
main
protease
Mpro
inhibitors.
Язык: Английский