3 research outputs found
REMD Simulations Reveal the Dynamic Profile and Mechanism of Action of Deleterious, Rescuing, and Stabilizing Perturbations to NBD1 from CFTR
Cystic
Fibrosis (CF) is a lethal, genetic disease caused by mutations
to the CFTR chloride channel. The most common CF causing mutation
is the deletion of F508 from the first Nucleotide Binding Domain (F508del-NBD1).
This mutation leads to a thermally unstable domain and a misfolded,
nonfunctioning CFTR. Replica Exchange MD simulations were used to
simulate seven NBD1 constructs including wt and F508del-NBD1 both
alone and in the presence of known rescuing mutations as well as F508del-NBD1
in complex with a known small (ligand) stabilizer. Analyzing the resulting
trajectories suggests that differences in the biochemical properties
of the constructs result from local and coupled differences in their
dynamic profiles. A comparative analysis of these profiles as well
as of the resulting trajectories reveals how the different perturbations
exert their deleterious, rescuing, and stabilizing effects on NBD1.
These simulations may therefore be useful for the design and mechanism-of-action
analysis of new NBD1 stabilizers
Synthesis and Biological Evaluation of Derivatives of Indoline as Highly Potent Antioxidant and Anti-inflammatory Agents
We
describe the preparation and evaluation of novel indoline derivatives
with potent antioxidant and anti-inflammatory activities for the treatment
of pathological conditions associated with chronic inflammation. The
indolines are substituted at position 1 with chains carrying amino,
ester, amide, or alcohol groups, and some have additional substituents,
Cl, MeO, Me, F, HO, or BnO, on the benzo ring. Concentrations of 1
pM to 1 nM of several compounds protected RAW264.7 macrophages against
H<sub>2</sub>O<sub>2</sub> induced cytotoxicity and LPS induced elevation
of NO, TNF-α, and IL-6. Several derivatives had anti-inflammatory
activity at 1/100th of the concentration of unsubstituted indoline.
Four compounds with ester, amine, amide, or alcohol side chains injected
subcutaneously in mice at a dose of 1 μmol/kg or less, like
dexamethasone (5.6 μmol/kg) prevented LPS-induced cytokine elevation
in the brain and peripheral tissues. Subcutaneous injection of 100
μmol/kg of these compounds caused no noticeable adverse effects
in mice during 3 days of observation
Synthesis and Biological Evaluation of Derivatives of Indoline as Highly Potent Antioxidant and Anti-inflammatory Agents
We
describe the preparation and evaluation of novel indoline derivatives
with potent antioxidant and anti-inflammatory activities for the treatment
of pathological conditions associated with chronic inflammation. The
indolines are substituted at position 1 with chains carrying amino,
ester, amide, or alcohol groups, and some have additional substituents,
Cl, MeO, Me, F, HO, or BnO, on the benzo ring. Concentrations of 1
pM to 1 nM of several compounds protected RAW264.7 macrophages against
H<sub>2</sub>O<sub>2</sub> induced cytotoxicity and LPS induced elevation
of NO, TNF-α, and IL-6. Several derivatives had anti-inflammatory
activity at 1/100th of the concentration of unsubstituted indoline.
Four compounds with ester, amine, amide, or alcohol side chains injected
subcutaneously in mice at a dose of 1 μmol/kg or less, like
dexamethasone (5.6 μmol/kg) prevented LPS-induced cytokine elevation
in the brain and peripheral tissues. Subcutaneous injection of 100
μmol/kg of these compounds caused no noticeable adverse effects
in mice during 3 days of observation