3 research outputs found
Potency Prediction of β‑Secretase (BACE-1) Inhibitors Using Density Functional Methods
Scoring
potency is a main challenge for structure based drug design.
Inductive effects of subtle variations in the ligand are not possible
to accurately predict by classical computational chemistry methods.
In this study, the problem of predicting potency of ligands with electronic
variations participating in key interactions with the protein was
addressed. The potency was predicted for a large set of cyclic amidine
and guanidine cores extracted from β-secretase (BACE-1) inhibitors.
All cores were of similar size and had equal interaction motifs but
were diverse with respect to electronic substitutions. A density functional
theory approach, in combination with a representation of the active
site of a protein using only key residues, was shown to be predictive.
This computational approach was used to guide and support drug design,
within the time frame of a normal drug discovery design cycle
Low estimated glomerular filtration rate is associated with poor outcomes in patients who suffered a large artery atherosclerosis stroke
[[abstract]]Objectives: The relationship between low estimated glomerular filtration rate (eGFR) and the outcome of ischemic stroke remains controversial, despite the close association between kidney dysfunction and atherosclerosis. Methods: This study conducted subgroup analysis using data from the prospective Taiwan Stroke Registry to investigate the relationship between eGFR at the time of admission and 6-month functional outcomes in patients with the large artery atherosclerotic (LAA) subtype of acute ischemic stroke. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS), and outcomes were defined as modified Rankin Scale and mortality status at 6 months post stroke. Results: Of the 8052 patients with the LAA subtype of acute ischemic stroke in this study, 3312 (41.1%) had eGFR 15 and eGFR <15mL/min/1.73m2, compared with those with NIHSS 0-5 and eGFR 60-119mL/min/1.73m2. Conclusions: Low eGFR was significantly and independently associated with 6-month functional outcomes and mortality in patients with the LAA subtype of acute ischemic stroke. The deleterious relationship between low eGFR levels and mortality following stroke was exacerbated by its synergistic association with stroke severity
Toward β‑Secretase‑1 Inhibitors with Improved Isoform Selectivity
BACE1
is responsible for the first step in APP proteolysis, leading
to toxic Aβ production, and has been indicated to play a key
role in the pathogenesis of Alzheimer’s disease. The related
isoform BACE2 is thought to be involved in processing of the pigment
cell-specific melanocyte protein. To avoid potential effects on pigmentation,
we investigated the feasibility for developing isoform-selective BACE1
inhibitors. Cocrystal structures of 47 compounds were analyzed and
clustered according to their selectivity profiles. Selective BACE1
inhibitors were found to exhibit two distinct conformational features
proximal to the flap and the S3 subpocket. Several new molecules were
designed and tested to make use of this observation. The combination
of a pyrimidinyl C-ring and a methylcyclohexyl element resulted in
lead molecule <b>28</b>, which exhibited ∼50-fold selectivity.
Compared to a nonselective BACE1/2 inhibitor, <b>28</b> showed
significantly less inhibition of PMEL processing in human melanocytes,
indicating good functional selectivity of this inhibitor class