2 research outputs found
PSW-Designer: An Open-Source Computational Platform for the Design and Virtual Screening of Photopharmacological Ligands
Photoswitchable (PSW) molecules offer an attractive opportunity
for the optical control of biological processes. However, the successful
design of such compounds remains a challenging multioptimization endeavor,
resulting in several biological target classes still relatively poorly
explored by photoswitchable ligands, as is the case for G protein-coupled
receptors (GPCRs). Here, we present the PSW-Designer, a fully open-source
computational platform, implemented in the KNIME Analytics Platform,
to design and virtually screen novel photoswitchable ligands for photopharmacological
applications based on privileged scaffolds. We demonstrate the applicability
of the PSW-Designer to GPCRs and assess its predictive capabilities
via two retrospective case studies. Furthermore, by leveraging bioactivity
information on known ligands, typical and atypical strategies for
photoswitchable group incorporation, and the increasingly structural
information available for biological targets, the PSW-Design will
facilitate the design of novel photoswitchable molecules with improved
photopharmacological properties and increased binding affinity shifts
upon illumination for GPCRs and many other protein targets
Large-Scale Biophysical Evaluation of Protein PEGylation Effects: In Vitro Properties of 61 Protein Entities
PEGylation is the
most widely used method to chemically modify
protein biopharmaceuticals, but surprisingly limited public data is
available on the biophysical effects of protein PEGylation. Here we
report the first large-scale study, with site-specific mono-PEGylation
of 15 different proteins and characterization of 61 entities in total
using a common set of analytical methods. Predictions of molecular
size were typically accurate in comparison with actual size determined
by size-exclusion chromatography (SEC) or dynamic light scattering
(DLS). In contrast, there was no universal trend regarding the effect
of PEGylation on the thermal stability of a protein based on data
generated by circular dichroism (CD), differential scanning calorimetry
(DSC), or differential scanning fluorimetry (DSF). In addition, DSF
was validated as a fast and inexpensive screening method for thermal
unfolding studies of PEGylated proteins. Multivariate data analysis
revealed clear trends in biophysical properties upon PEGylation for
a subset of proteins, although no universal trends were found. Taken
together, these findings are important in the consideration of biophysical
methods and evaluation of second-generation biopharmaceutical drug
candidates