Low-toxicity nanoMolar scaffolds with hundreds of variants generated by computational co-evolution into prokaryotic potassium channel cavities
Published: Jan. 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.
Language: Английский
Ligands docking to ORF8 by co-evolution. Could they reduce the inflammation levels induced by SARS-COV-2 infections?
Published: Nov. 23, 2023
The
unique
ORF8
is
an
asymmetric
homodimer
accessory
protein
of
SARS-COV-2
implicated
in
pathogenesis
by
activating
excesive
human
inflammation
causing
numerous
deaths.
There
no
approved
drug
targeting
ORF8,
nor
it
known
whether
any
anti-ORF8
drugs
could
reduce
coronavirus-induced
inflammation.
Computationally
combining
ligand
co-evolution
parent
molecules
with
affinity-ranking
consensus
docking,
children
candidates
for
cavities
and
ligands
were
generated.
Targeting
the
interface
cavity
highest
affinity
scaffolds,
hundreds
grandchildren
generated
specificity-toxicity
controlled
additional
co-evolutions
to
predict
nanoMolar
affinities,
high
specificities
low
toxicity
risks.
Although
remaining
hypothetical
without
experimental
confirmation,
these
constitute
a
new
methodological
attempt
search
drug-like
interfere
SARS-COV-2-dependent
excessive
Language: Английский
Star-shaped conformers generated by co-evolutionary docking predict cross-fitting glycoprotein trimer pre-fusion interfaces on VHSV fish rhabdovirus
Published: April 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
Language: Английский
Tailoring evolved-ligands to Plasmodium circumsporozoite-protein
Published: June 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
Language: Английский