6 research outputs found
MOESM2 of Spectrophores as one-dimensional descriptors calculated from three-dimensional atomic properties: applications ranging from scaffold hopping to multi-target virtual screening
Additional file 2. Experimental procedures for the biochemical assay
MOESM1 of Spectrophores as one-dimensional descriptors calculated from three-dimensional atomic properties: applications ranging from scaffold hopping to multi-target virtual screening
Additional file 1. Ring fragments and their corresponding clusters
Discovery and SAR of Novel and Selective Inhibitors of Urokinase Plasminogen Activator (uPA) with an Imidazo[1,2‑<i>a</i>]pyridine Scaffold
Urokinase plasminogen activator (uPA)
is a biomarker and therapeutic
target for several cancer types. Its inhibition is regarded as a promising,
noncytotoxic approach in cancer therapy by blocking growth and/or
metastasis of solid tumors. Earlier, we reported the modified substrate
activity screening (MSAS) approach and applied it for the identification
of fragments with affinity for uPA’s S1 pocket. Here, these
fragments are transformed into a novel class of uPA inhibitors with
an imidazo[1,2-<i>a</i>]pyridine scaffold. The SAR for uPA
inhibition around this scaffold is explored, and the best compounds
in the series have nanomolar uPA affinity and selectivity with respect
to the related trypsin-like serine proteases (thrombin, tPA, FXa,
plasmin, plasma kallikrein, trypsin, FVIIa). Finally, the approach
followed for translating fragments into small molecules with a decorated
scaffold architecture is conceptually straightforward and can be expected
to be broadly applicable in fragment-based drug design
Tozasertib Analogues as Inhibitors of Necroptotic Cell Death
Receptor
interacting protein kinase 1 (RIPK1) plays a crucial role in tumor
necrosis factor (TNF)-induced necroptosis, suggesting that this pathway
might be druggable. Most inhibitors of RIPK1 are classified as either
type II or type III kinase inhibitors. This opened up some interesting
perspectives for the discovery of novel inhibitors that target the
active site of RIPK1. Tozasertib, a type I pan-aurora kinase (AurK)
inhibitor, was found to show a very high affinity for RIPK1. Because
tozasertib presents the typical structural elements of a type I kinase
inhibitor, the development of structural analogues of tozasertib is
a good starting point for identifying novel type I RIPK1 inhibitors.
In this paper, we identified interesting inhibitors of mTNF-induced
necroptosis with no significant effect on AurK A and B, resulting
in no nuclear abnormalities as is the case for tozasertib. Compounds <b>71</b> and <b>72</b> outperformed tozasertib in an in vivo
TNF-induced systemic inflammatory response syndrome (SIRS) mouse model
2,6-Di(arylamino)-3-fluoropyridine Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors
New
non-nucleoside reverse transcriptase inhibitors (NNRTI), which
are similar in structure to earlier described di(arylamino)pyrimidines
but featuring a 2,6-di(arylamino)-3-fluoropyridine, 2,4-di(arylamino)-5-fluoropyrimidine,
or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted
pyrimidine moiety, are reported. The short and practical synthesis
of novel NNRTI relies on two sequential Pd-catalyzed aminations as
the key steps. It is demonstrated through direct comparison with reference
compounds that the presence of a fluorine atom increases the in vitro
anti-HIV activity, both against the wild type virus and drug-resistant
mutant strains
Mean biomass-per-unit-effort (BPUE) of the eleven most commonly caught species from 2007–2013.
<p>BPUE is represented as the estimated weight (kg) of fishes caught-per-angler-hour, using two hooks per line. Solid lines illustrate catch rates from marine protected areas (MPA), whereas dashed lines represent values from associated reference (REF) sites. Error bars denote one standard error above and below the mean.</p