The Fe-MAN Challenge: Ferrates-Microkinetic Assessment of Numerical Quantum Chemistry.

Organometallic species, such as organoferrate ions, are prototypical nucleophiles prone to reacting with a wide range of electrophiles, including proton donors. In solution, the operation of dynamic equilibria and the simultaneous presence of several organometallic species severely complicate the analysis of these fundamentally important reactions. This can be overcome by gas-phase experiments on mass-selected ions, which allow for the determination of the microscopic reactivity of the target species. In this contribution, we focus on the reactivity of a series of trisarylferrate complexes toward 2,2,2-trifluoroethanol and 2,2-difluoroethanol. By means of mass-spectrometric measurements, we determined the experimental bimolecular rate constants kexp of the gas-phase protolysis reactions of the trisarylferrate anions FePh3- and FeMes3- with the aforementioned acids. Based on these experiments, we carried out a dual blind challenge, inviting theoretical groups to submit their best predictions for the activation barriers and/or theoretical rate constants ktheo. This provides a unique opportunity to evaluate different computational protocols under minimal bias and sets the stage for further benchmarking of quantum chemical methods and data-driven approaches in the future.

Virtual Screening Expands the Non-Natural Amino Acid Palette for Peptide Optimization.

Peptides are an important modality in drug discovery. While current peptide optimization focuses predominantly on the small number of natural and commercially available non-natural amino acids, the chemical spaces available for small molecule drug discovery are in the billions of molecules. In the present study, we describe the development of a large virtual library of readily synthesizable non-natural amino acids that can power the virtual screening protocols and aid in peptide optimization. To that end, we enumerated nearly 380 thousand amino acids and demonstrated their vast chemical diversity compared to the 20 natural and commercial residues. Furthermore, we selected a diverse ten thousand amino acid subset to validate our virtual screening workflow on the Keap1-Neh2 complex model system. Through in silico mutations of Neh2 peptide residues to those from the virtual library, our docking-based protocol identified a number of possible solutions with a significantly higher predicted affinity toward the Keap1 protein. This protocol demonstrates that the non-natural amino acid chemical space can be massively extended and virtually screened with a reasonable computational cost.

Sensor dimer disruption as a new mode of action to block the IRE1-mediated unfolded protein response.

The unfolded protein response (UPR) is activated to cope with an accumulation of improperly folded proteins in the Endoplasmic reticulum (ER). The Inositol requiring enzyme 1α (IRE1α) is the most evolutionary conserved transducer of the UPR. Activated IRE1 forms 'back-to-back'-dimers that enables the unconventional splicing of X-box Binding Protein 1 (XBP1) mRNA. The spliced XBP1 (XBP1s) mRNA is translated into a transcription factor controlling the expression of UPR target genes. Herein, we report a detailed in silico screening specifically targeting for the first time the dimer interface at the IRE1 RNase region. Using the database of FDA approved drugs, we identified four compounds (neomycin, pemetrexed, quercitrin and rutin) that were able to bind to and distort IRE1 RNase cavity. The activity of the compounds on IRE1 phosphorylation was evaluated in HEK293T cells and on IRE1 RNase activity using an in vitro fluorescence assay. These analyzes revealed sub-micromolar IC50 values. The current study reveals a new and unique mode of action to target and block the IRE1-mediated UPR signaling, whereby we may avoid problems associated with selectivity occurring when targeting the IRE1 kinase pocket as well as the inherent reactivity of covalent inhibitors targeting the RNase pocket.