4 research outputs found
Preparation of Freestanding Conjugated Microporous Polymer Nanomembranes for Gas Separation
Conjugated microporous polymers (CMPs)
have attracted much interest
due to their intrinsic porosity, outstanding stability, and high variability.
However, the processing of these materials for membrane application
has been limited due to their insoluble nature when synthesized as
bulk material. Here we report the synthesis of freestanding CMP-nanomembranes
via layer-by-layer growth of a āclickā based conjugated
microporous polymer on a sacrificial substrate. After dissolution
of the substrate the CMP-nanomembrane can be transferred to porous
substrates and continuously cover holes of up to 50 Ī¼m diameter.
The CMP-nanomembranes appear defect-free as inferred from high selectivity
values obtained from gas permeation experiments and from electrochemical
investigation in the presence of ferrocene. The presented synthesis
method represents a versatile strategy to incorporate CMP materials
in functional devices for membrane separation, catalysis, or organic
electronics
Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach
A structure-guided hybridization
approach using two privileged
substructures gave instant access to a new series of tankyrase inhibitors.
The identified inhibitor <b>16</b> displays high target affinity
on tankyrase 1 and 2 with biochemical and cellular IC<sub>50</sub> values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity
toward other poly (ADP-ribose) polymerase enzymes. The identified
inhibitor shows a favorable in vitro ADME profile as well as good
oral bioavailability in mice, rats, and dogs. Critical for the approach
was the utilization of an appropriate linker between 1,2,4-triazole
and benzimidazolone moieties, whereby a cyclobutyl linker displayed
superior affinity compared to a cyclohexane and phenyl linker
Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach
A structure-guided hybridization
approach using two privileged
substructures gave instant access to a new series of tankyrase inhibitors.
The identified inhibitor <b>16</b> displays high target affinity
on tankyrase 1 and 2 with biochemical and cellular IC<sub>50</sub> values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity
toward other poly (ADP-ribose) polymerase enzymes. The identified
inhibitor shows a favorable in vitro ADME profile as well as good
oral bioavailability in mice, rats, and dogs. Critical for the approach
was the utilization of an appropriate linker between 1,2,4-triazole
and benzimidazolone moieties, whereby a cyclobutyl linker displayed
superior affinity compared to a cyclohexane and phenyl linker
Probing Factor Xa ProteināLigand Interactions: Accurate Free Energy Calculations and Experimental Validations of Two Series of High-Affinity Ligands
The accurate prediction of proteināligand binding
affinity
belongs to one of the central goals in computer-based drug design.
Molecular dynamics (MD)-based free energy calculations have become
increasingly popular in this respect due to their accuracy and solid
theoretical basis. Here, we present a combined study which encompasses
experimental and computational studies on two series of factor Xa
ligands, which enclose a broad chemical space including large modifications
of the central scaffold. Using this integrated approach, we identified
several new ligands with different heterocyclic scaffolds different
from the previously identified indole-2-carboxamides that show superior
or similar affinity. Furthermore, the so far underexplored terminal
alkyne moiety proved to be a suitable non-classical bioisosteric replacement
for the higher halogenāĻ aryl interactions. With this
challenging example, we demonstrated the ability of the MD-based non-equilibrium
free energy calculation approach for guiding crucial modifications
in the lead optimization process, such as scaffold replacement and
single-site modifications at molecular interaction hot spots