Anticoagulant rodenticide novel candidates predicted by evolutionary docking
Опубликована: Авг. 1, 2023
To
generate
high-throughoutput
numbers
of
putative
anticoagulant
rodenticides,
a
computational
evolutionary
method
has
been
applied.
In
particular,
the
previously
described
DataWarrior
Build-Evolutionary-Library
was
optimized
to
randomly
made-on-demand
brodifacoum-derived
children
libraries
exploring
new
chemotypes
for
candidates.
The
generated
were
selected
by
fitting
brodifacoum-docking
cavity
rat-VKORC1
(vitamin
K
epoxide
reductase
complex
1)
alphafold-modeled
using
recent
crystallographic
human-VKORC1
complex.
non-toxic
predicting
highest
affinities
(lowest
docking-scores)
wild
type
and
resistant
rat
mutants
(Spanish
European)
lowest
human
VKORC1,
consensed
AutoDockVina
docking
identify
with
increased
accuracy
those
candidates
nanomolar
affinities.
resulting
layout
library
150
provided
multi-threshold-adjustable
filters,
constitute
an
step
forward
towards
in
silico
fine-tuning
elimination
any
other
off-target
biological
species.
Chemical
synthesis
pathway
predictions
experimental
validations
remain
be
done
Язык: Английский
Exploring non-toxic co-evolutionary docking
Опубликована: Сен. 27, 2023
Drug-spaces
of
nine
crystallographic
protein
/
ligand
models
have
been
comparatively
explored
by
including
Toxicity
Risk
assessment
during
computational
co-evolution.
Tens
thousands
children
were
randomly
generated
from
parent
ligands
and
iteratively
selected
for
higher
affinities,
increased
specificities
low
using
DataWarrior
Build
Evolutionary
Library
algorithms,
mimicking
natural
evolution.
Only
a
few
hours
co-evolution
~
2-fold
the
numbers
non-toxic
children.
Top-leads
predicted
drug-like
properties,
nanoMolar
affinities
(confirmed
AutoDockVina),
specificities,
absence
known
toxicities,
similar
docking
to
their
initial
binding
cavities.
Tables
provided
with
multi-threshold-adjustable
filters
alternative
in
silico
explorations
this
new
"co-evolutionary
docking"
tool.
Язык: Английский
Low-toxicity nanoMolar scaffolds with hundreds of variants generated by computational co-evolution into prokaryotic potassium channel cavities
Опубликована: Янв. 17, 2024
Human
potassium
channels
(Kir)
are
implicated
in
numerous
dysfunction
diseases
genetically
affecting
cardiovascular,
skeletal-muscle
and/or
synaptic-neuronal
functions.
Variations
Kir
sequences,
organ
distribution
differences
and
toxicity
of
some
their
known
inhibitors,
require
alternative
drugs
to
interfere
specifically
with
each
human
molecular
species.
In
this
work,
a
prokaryotic
asymmetric
transmembrane
homotetramer
(K+)
channel
protein
highly
homologous
Kirs
has
been
used
as
model.
Computational
methods
combining
parent
co-evolutions
confirmed
by
consensus
docking,
were
explored
possible
prove-of-concept
generate
rather
than
screen
for
KcsA
docking-ligands.
The
explorations
the
central
cavity
interface
lipid-binding
shallow-grooves,
predicted
specific
novel
scaffolds
low-toxicity
risks,
displaying
hundreds
variations
new
within
nanoMolar-ranged
affinities.
Experimental
validation
additional
computational
research
on
could
be
attempted
future.
Язык: Английский
Could Acinetobacter baumannii Lol-abaucin docking be improved?
Опубликована: Июнь 28, 2023
To
explore
alternative
abaucin
antibiotics
predicting
nanomolar
affinities
against
Acinetobacter
baumannii,
thousands
of
virtual
abaucin-derived
molecules
were
randomly
generated
and
selected.
For
this,
alphafold-modeled
A.baumannii
lipoprotein
outer
membrane
localization
(Lol)
complex
proteins
targeted
by
DataWarrior
"build
evolutionary
libraries".
Abaucin-children
libraries
from
the
abaucin-parent
iteratively
selecting
those
higher
to
most
probable
LolCE
docking-cavity.
improve
accuracies,
~4000
abaucin-children
docking-scores
consensed
with
AutoDockVina.
The
resulting
laydown
table
provided
filter
sliders
would
allow
user-criteria
be
applied.
One
example
explored
candidates
both
(to
favor
putative
antibiotics)
lower
E.coli
narrow-bacterial
spectrum
hits).
Despite
being
highly
hypothetical,
some
these
chemotypes
may
constitute
another
step
towards
exploring
possible
improvements
for
anti-A.baumannii
antibiotics.
Язык: Английский
Star-shaped conformers generated by co-evolutionary docking predict cross-fitting glycoprotein trimer pre-fusion interfaces on VHSV fish rhabdovirus
Опубликована: Апрель 26, 2024
Despite
the
abundant
diseases
caused
by
rhabdoviruses
on
plants,
animals
and
men,
there
are
no
approved
therapeutic
drugs.
This
work
targeted
viral
hemorrhagic
septicemia
viruses
(VHSV),
a
group
of
representative
causing
devastating
world-wide
fish
farmed-species.
In
particular,
their
glycoprotein
(gpGVHSV)
trimers
were
computationally
at
its
earliest
pre-fusion
inner
interface.
Co-evolution
initiated
from
an
optimized
2D-molecular
parent
corresponding
gpGVHSV
-conformer
3D
cavity,
generated
tens
thousands
raw-children,
selected
hundreds
cross-fitting
conformer
variations
in
few
scaffolds.
Their
predicted
drug-like
high
affinities
nanoMolar
ranges,
low
toxicities
targeting
interface
confirmed
independent
algorithms
Язык: Английский
Tailoring evolved-ligands to Plasmodium circumsporozoite-protein
Опубликована: Июнь 3, 2024
To
prevent
malaria
deathly
infections,
the
Plasmodium
circumsporozoite
major
protein
(CSP)
have
been
targeted
world-wide
to
develop
most
recent
vaccines
inducing
anti-CSP
antibodies.
In
contrast,
drug-like
complement
that
tool-box,
remain
underdeveloped.
Despite
tridimensional
coat
of
disordered-repeats,
computational
predictions
mimicking
natural
co-evolution
tailored
evolved
ligands
adapt
ordered
CSP
cavities.
Tens
thousands
parent-generated
raw-candidates
selected
hundreds
fitted-children
conformers
predicting
low
nanoMolar
affinities,
toxicities,
and
cross-docking
N-terminal
signal
peptide
with
C-terminal
α-helices
or
docking
These
repeat-independent
predictions,
could
provide
some
proof-of-concept
examples
for
basic
in
vitro
experimentation
Язык: Английский
Anticoagulant rodenticide novel candidates predicted by evolutionary docking
Опубликована: Июнь 2, 2023
The
evolutionary
docking
generation
of
high
numbers
potentially
novel
anticoagulant
rodenticides
is
described
here.
In
particular,
made-on-demand
libraries
were
generated
by
randomly
introducing
small
molecular
variations
into
alphafold-modeled
brodifacoum-rat
VKORC1
binding-cavity.
For
evolution
the
brodifacoum
parent,
criteria
mainly
optimized
to
fit-dock
cavity.
Libraries
specific
brodifacoum-children
selected
pooling
those
predicting
higher
affinities
(lower
binding-scores)
at
various
weights.
filtered
for
known
toxicities,
desirable
affinity
recently
identified
spanish
resistance
rat
mutants
and
undesirable
human
VKORC1.
flexible
threshold-adjustable
new
chemotype
constitute
an
step
forward
towards
further
in
silico
fine-tuning
computationally
reduce
other
possible
unspecific
off-target
ecological
impacts
Язык: Английский