Abstract This paper investigates four of the constitutional isomers of Si2H2+, namely the butterfly, vinylidene‐like, monobridged, and trans structures. These isomer geometries were all studied using the CCSD(T) method with basis sets as large as cc‐pV5Z. Higher level methods CCSDT and CCSDT(Q) were used for final energetics. It is found that the butterfly isomer has the lowest energy, followed by vinylidene‐like and monobridged structures; the trans structure has the highest energy of the four. All structures were compared with their neutral counterparts. Partial charges are computed and it is found that all isomers share the positive charge between the silicon atoms. NBO analysis shows that the cation Si−Si bond order is reduced by 0.5 relative to the neutral versions of the same isomer in the case of the butterfly, vinylidene‐like, and monobridged; and reduced by 0.6 for the trans isomer. Vibrational frequencies, infrared intensities, and dipole moments are predicted to encourage the spectroscopic identification of Si2H2+.

It is argued that each of the three key steps in drug discovery, (i) reaction screening to find successful routes to desired drug candidates, (ii) scale up of the synthesis to produce amounts adequate for testing, and (iii) bioactivity assessment of the candidate compounds, can all be performed using mass spectrometry (MS) in a sequential fashion. The particular ionization method of choice, desorption electrospray ionization (DESI), is both an analytical technique and a procedure for small-scale synthesis. It is also highly compatible with automation, providing for high throughput in both synthesis and analysis. Moreover, because accelerated reactions take place in the secondary DESI microdroplets generated from individual reaction mixtures, this allows either online analysis by MS or collection of the synthetic products by droplet deposition. DESI also has the unique advantage, amongst spray-based MS ionization methods, that complex buffered biological solutions can be analyzed directly, without concern for capillary blockage. Here, all these capabilities are illustrated, the unique chemistry at droplet interfaces is presented, and the possible future implementation of DESI-MS based drug discovery is discussed.

Abstract The activation of small molecules by silylenes bearing unique electronic properties has been well established in the past few decades. Here, we disclose the reactivity study of acyclic imino(silyl)silylene 1 with an N‐heterocyclic imine ligand (NHI) towards various small molecules. Silylene 1 undergoes facile activation of gaseous molecules like dihydrogen, ethylene, and carbon dioxide. While the cycloaddition of carbonyl compounds to 1 was shown as a straightforward synthetic approach of oxasilacycles, reaction with silane as well as borane led to the corresponding E−H (E=Si, B) insertion products. Moreover, reaction with heavier chalcogens allow the isolation of neutral three‐coordinate silicon‐heavier chalcogen double bond complexes.

Abstract Many types of bacteria engage in complex collective behaviors, often controlled by a form of cell‐cell communication mediated by diffusible signal molecules called quorum sensing (QS). Each individual produces and responds to these diffusible signaling molecules, inferring properties of their environment, and modulating the regulation of hundreds of downstream genes in response. A threshold concept is ingrained in the QS literature following the use of the legal ‘quorum’ analogy, where populations of bacteria are synchronously sub‐quorate below a threshold population size or synchronously quorate above a threshold population size. However, a growing body of literature highlights that QS can produce more nuanced, graded responses to environmental variation, implying there is no simple threshold ‘quorum’ on either the single cell or population scale. In this commentary, we discuss reaction norms as a tool to quantify and compare QS‐controlled behaviors in an environmental context.

Small molecule inhibitors of the intracellular serine peptidases DPP8 and DPP9 (DPP8/9) activate the NLRP1 and CARD8 inflammasomes, but the key DPP8/9 substrates have not yet been identified. DPP8/9 cleave after proline to remove N-terminal dipeptides from peptides or proteins, and studies using pseudo-peptide reporter substrates have suggested that these enzymes may play key roles in the catabolism of many proline-containing peptides generated by the proteasome. Here, we evaluated the degradation of a wide array of actual peptides in cell lysates, and discovered that DPP8/9 are not in fact involved in the processing of the vast majority of proline-containing peptides. Overall, these results indicate that DPP8/9 have a much more limited substrate scope than previously thought, and likely specifically cleave some critically important, but as yet unknown, intracellular peptide or protein that regulates inflammasome activation.

Chemical probes are invaluable tools to investigate biological processes and can serve as lead molecules for the development of new therapies. However, despite their utility, only a fraction of human proteins have selective chemical probes, and more generally, our knowledge of the "chemically-tractable" proteome is limited, leaving many potential therapeutic targets unexploited. To help address these challenges, powerful chemical proteomic approaches have recently been developed to globally survey the ability of proteins to bind small molecules (i. e., ligandability) directly in native systems. In this review, we discuss the utility of such approaches, with a focus on the integration of chemoproteomic methods with fragment-based ligand discovery (FBLD), to facilitate the broad mapping of the ligandable proteome while also providing starting points for progression into lead chemical probes.

Abstract There has been a surge of interest and efforts in the discovery of covalent ligands for diverse proteins as tool compounds or therapeutic candidates in recent years. We present two studies that involve applications of a target‐centric approach and a ligand‐centric approach toward covalent ligand discovery. By targeting a rare cysteine residue in a receptor tyrosine kinase EphB3, we were able to rapidly identify potent inhibitors of EphB3 with extraordinary proteomic selectivity supported by activity‐based probe profiling. While characterizing an activity‐based probe intended for EphB3 using ABPP, we made a surprising discovery that its primary cellular target was a catalytic subunit of V‐ATPase through its covalent engagement with a cryptic pocket on V‐ATPase. These two approaches will be increasingly used in combination to develop covalent ligands with high potency and yield comprehensive target profiles to accelerate the rate of therapeutic discovery in the future.

Abstract Wearing a silicone wristband exposes the internal surface of the wristband to glucose, lipids, and metabolites (metabolome) found in sweat and the external surface to occupational and environmental factors that could impact health found in the air (exposome). We use silicone wristband electrospray ionization mass spectrometry (SWESI‐MS) to monitor these species. A 20‐μL drop of a (1 : 1, v/v) water:methanol solution is sufficient to extract abundant metabolites and contacting chemicals derived from ingestion of drink, smoke, diet, drug, and air pollution exposure. A wide coverage of species is successfully detected and identified from a worn wristband including caffeine, glucose, nicotine, reserpine, lactate, phosphocreatinine, oleic acid, and urea. The signal from a triangular wristband surface triggered by applying a voltage of 5 kV to form a spray remains stable for at least 2 minutes. The response is linear from 10 pM to 100 μM. The SWESI‐MS method offers the advantages of onsite sampling, no preprocessing, simple testing, and automatic high‐dimensional data searching. It can be used for simultaneously monitoring hazardous chemical contamination and abnormal expression of sweat‐secreted metabolites that are indicative of some physiological condition.

Abstract East Lansing, MI 48824 Cyclic di‐nucleotides (CDNs) are central signaling molecules in organisms spanning the tree of life. In bacteria, CDNs mediate many important physiological functions such as biofilm formation, motility, and virulence. CDNs are also implicated in activation of cellular biological defense systems in both bacteria and eukaryotes. In bacteria, the CDN 3’3’‐cyclic GMP‐AMP (3’3’‐cGAMP) activates a putative phage defense system in Vibrio cholerae and controls central physiological processes in Geobacter sulfurreducens and Bdellovibrio bacteriovorus. Therefore, access to a rapid, accurate 3’3’‐cGAMP quantification assay would enable further studies of this signaling molecule. Here, we describe validation of a novel 3’3’‐cGAMP enzyme linked immunoassay (ELISA) developed by Cayman Chemicals. We demonstrate that the concentrations of 3’3’‐cGAMP determined by this ELISA strongly correlate with those obtained using liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Furthermore, during these studies we show that the V. cholerae 3’3’‐cGAMP synthase, DncV, when expressed by itself in Escherichia coli, is not activated by phage infection.

Abstract Host‐associated and environmental microbiomes play central roles in human health, biogeochemical cycling, response to ecosystem change, and agriculture. Scientific approaches that can reveal the functional activities that contribute to observed phenotypes are needed in microbiome research. Broad characterization of the functional activity of microbes within microbiomes is currently hampered by approaches that rely on inference of function from metagenomes or indirect measurements. Activity‐based protein profiling is uniquely positioned to overcome these challenges and reveal the protein‐level mechanisms associated with microbiome phenotypes. In this review we describe the progress made to date using ABPP in gut microbiome, plant‐microbe interaction, and soil microbiome research, and suggest how ABPP data can be coupled with advanced computational methods to enable phenotype prediction and bioengineering of microbiomes for applied purposes.