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
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