6 research outputs found
Linker-Dependent Folding Rationalizes PROTAC Cell Permeability
Proteolysis-targeting chimeras (PROTACs) must be cell
permeable
to reach their target proteins. This is challenging as the bivalent
structure of PROTACs puts them in chemical space at, or beyond, the
outer limits of oral druggable space. We used NMR spectroscopy and
molecular dynamics (MD) simulations independently to gain insights
into the origin of the differences in cell permeability displayed
by three flexible cereblon PROTACs having closely related structures.
Both methods revealed that the propensity of the PROTACs to adopt
folded conformations with a low solvent-accessible 3D polar surface
area in an apolar environment is correlated to high cell permeability.
The chemical nature and the flexibility of the linker were essential
for the PROTACs to populate folded conformations stabilized by intramolecular
hydrogen bonds, π–π interactions, and van der Waals
interactions. We conclude that MD simulations may be used for the
prospective ranking of cell permeability in the design of cereblon
PROTACs
Linker-Dependent Folding Rationalizes PROTAC Cell Permeability
Proteolysis-targeting chimeras (PROTACs) must be cell
permeable
to reach their target proteins. This is challenging as the bivalent
structure of PROTACs puts them in chemical space at, or beyond, the
outer limits of oral druggable space. We used NMR spectroscopy and
molecular dynamics (MD) simulations independently to gain insights
into the origin of the differences in cell permeability displayed
by three flexible cereblon PROTACs having closely related structures.
Both methods revealed that the propensity of the PROTACs to adopt
folded conformations with a low solvent-accessible 3D polar surface
area in an apolar environment is correlated to high cell permeability.
The chemical nature and the flexibility of the linker were essential
for the PROTACs to populate folded conformations stabilized by intramolecular
hydrogen bonds, π–π interactions, and van der Waals
interactions. We conclude that MD simulations may be used for the
prospective ranking of cell permeability in the design of cereblon
PROTACs
Efficient Isotope Editing of Proteins for Site-Directed Vibrational Spectroscopy
Vibrational
spectra contain unique information on protein structure
and dynamics. However, this information is often obscured by spectral
congestion, and site-selective information is not available. In principle,
sites of interest can be spectrally identified by isotope shifts,
but site-specific isotope labeling of proteins is today possible only
for favorable amino acids or with prohibitively low yields. Here we
present an efficient cell-free expression system for the site-specific
incorporation of any isotope-labeled amino acid into proteins. We
synthesized 1.6 mg of green fluorescent protein with an isotope-labeled
tyrosine from 100 mL of cell-free reaction extract. We unambiguously
identified spectral features of the tyrosine in the fingerprint region
of the time-resolved infrared absorption spectra. Kinetic analysis
confirmed the existence of an intermediate state between photoexcitation
and proton transfer that lives for 3 ps. Our method lifts vibrational
spectroscopy of proteins to a higher level of structural specificity
Antiviral Rotenoids and Isoflavones Isolated from <i>Millettia</i> <i>oblata</i> ssp. <i>teitensis</i>
Three new (1–3) and
six known
rotenoids (5–10), along with three
known isoflavones (11–13), were isolated
from the leaves of Millettia oblata ssp. teitensis. A new glycosylated isoflavone (4), four known isoflavones (14–18), and one known chalcone (19) were isolated from the
root wood extract of the same plant. The structures were elucidated
by NMR and mass spectrometric analyses. The absolute configuration
of the chiral compounds was established by a comparison of experimental
ECD and VCD data with those calculated for the possible stereoisomers.
This is the first report on the use of VCD to assign the absolute
configuration of rotenoids. The crude leaves and root wood extracts
displayed anti-RSV (human respiratory syncytial virus) activity with
IC50 values of 0.7 and 3.4 μg/mL, respectively. Compounds 6, 8, 10, 11, and 14 showed anti-RSV activity with IC50 values of
0.4–10 μM, while compound 3 exhibited anti-HRV-2
(human rhinovirus 2) activity with an IC50 of 4.2 μM.
Most of the compounds showed low cytotoxicity for laryngeal carcinoma
(HEp-2) cells; however compounds 3, 11,
and 14 exhibited low cytotoxicity also in primary lung
fibroblasts. This is the first report on rotenoids showing antiviral
activity against RSV and HRV viruses
A cross-platform format to associate NMR-extracted data (NMReDATA) to chemical structures
Poster presented at EUROMAR Meeting July 201
A cross-platform format to associate NMR-extracted data (NMReDATA) to chemical structures
Poster presented at SMASHNMR meeting Sep 201