Evaluation of Cereblon-Directing Warheads for the Development of Orally Bioavailable PROTACs.

PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall degradation and antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor pharmacokinetic profile. To further demonstrate the PG utility, we describe here optimization efforts that led to the discovery of an orally bioavailable BET-PROTAC SJ44236 (), and results of a comprehensive comparative study with analogues containing alternative CRBN-directing warheads.

Correlation of chromatographic performance with morphological features of organic polymer monoliths.

Monoliths are considered to be a low pressure alternative to particle packed columns for liquid chromatography (LC). However, the chromatographic performance of organic monoliths, in particular, has still not reached the level of particle packed columns. Since chromatographic performance can be attributed to morphological features of the monoliths, in-situ characterization of the monolith structure in three dimensions would provide valuable information that could be used to help improve performance.

A polarizable reactive force field for water to enable molecular dynamics simulations of proton transport.

A new polarizable water model is developed for molecular dynamics (MD) simulations of the proton transport process. The interatomic potential model has three important submodels corresponding to electrostatic interactions, making and breaking of covalent bonds, and treatment of electron exchange and correlation through a van der Waals potential. A polarizable diffuse charge density function was used to describe Coulombic interactions between atoms.

Chemical potential perturbation: extension of the method to lattice sum treatment of intermolecular potentials.

The recently developed chemical potential perturbation (CPP) method [S. G. Moore and D.

Chemical potential perturbation: a method to predict chemical potentials in periodic molecular simulations.

A new method, called chemical potential perturbation (CPP), has been developed to predict the chemical potential as a function of density in periodic molecular simulations. The CPP method applies a spatially varying external force field to the simulation, causing the density to depend upon position in the simulation cell. Following equilibration the homogeneous (uniform or bulk) chemical potential as a function of density can be determined relative to some reference state after correcting for the effects of the inhomogeneity of the system.

Intrinsic autotrophic biomass yield and productivity in algae: modeling spectral and mixing-rate dependence.

For non-inhibitory irradiances, the rate of algal biomass synthesis was modeled as the product of the algal autotrophic yield Φ(DW) and the flux of photons absorbed by the culture, as described using Beer-Lambert law. As a contrast to earlier attempts, the use of scatter-corrected extinction coefficients enabled the validation of such approach, which bypasses determination of photosynthesis-irradiance (PI) kinetic parameters. The broad misconception that PI curves, or the equivalent use of specific growth rate expressions independent of the biomass concentration, can be extended to adequately model biomass production under light-limitation is addressed.

Improved implementation of Kirkwood-Buff solution theory in periodic molecular simulations.

Kirkwood-Buff (KB) solution theory is a means to obtain certain thermodynamic derivatives from knowledge of molecular distributions. In actual practice the required integrals over radial distribution functions suffer inaccuracies due to finite-distance truncation effects and their use in closed systems. In this work we discuss how best to minimize these inaccuracies under traditional KB theory.

MPSA effects on copper electrodeposition investigated by molecular dynamics simulations.

In superconformal filling of copper-chip interconnects, organic additives are used to fill high-aspect-ratio trenches or vias from the bottom up. In this study we report on the development of intermolecular potentials and use molecular dynamics simulations to provide insight into the molecular function of an organic additive (3-mercaptopropanesulfonic acid or MPSA) important in superconformal electrodeposition. We also investigate how the presence of sodium chloride affects the surface adsorption and surface action of MPSA as well as the charge distribution in the system.

DNA-templated three-branched nanostructures for nanoelectronic devices.

Three-branched DNA molecules have been designed and assembled from oligonucleotide components. These nucleic acid constructs contain double- and single-stranded regions that control the hybridization behavior of the assembly. Specific localization of a single streptavidin molecule at the center of the DNA complex has been investigated as a model system for the directed placement of nanostructures.