HTS by NMR of Combinatorial Libraries: A Fragment-Based Approach to Ligand Discovery

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Highlights? HTS by NMR combines protein NMR and combinatorial chemistry to screen large libraries ? The approach is best suited to identify ligands to protein-protein interactions ? The method enables a rapid assessment of the druggability of a given target ? We applied the method to a test case and to derive potent and selective EphA4 ligands     

Bayesian Models Leveraging Bioactivity and Cytotoxicity Information for Drug Discovery

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Highlights? Including efficacy and cytotoxicity data improves performance of computational models ? Antitubercular hits, leads, and chemical probes were identified using Bayesian models ? The most advanced compound provides significant in vitro activity and in vivo safety ? Demonstrated orders-of-magnitude higher hit rates than current HTS practices     

The Natural Anticancer Compounds Rocaglamides Inhibit the Raf-MEK-ERK Pathway by Targeting Prohibitin 1 and 2

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Highlights? The natural anticancer compound rocaglamide directly binds to PHB1 and PHB2 ? Rocaglamide blocks PHB-mediated activation of CRaf-MEK-ERK pathway and cancer proliferation ? Rocaglamide may serve as a new type of anticancer agent ? Rocaglamide may serve as a new molecular tool for studying PHB-mediated cellular functions     

Discovery of an Iron-Regulated Citrate Synthase in Staphylococcus aureus

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Highlights? Staphylococcus aureus SbnG is discovered to be an iron-regulated citrate synthase ? SbnG provides citrate for synthesis of the citrate siderophore staphyloferrin B ? Staphyloferrin B can be synthesized in vitro using purified enzymes ? SbnG inhibitors identified     

Indirubin Derivatives Modulate TGFβ/BMP Signaling at Different Levels and Trigger Ubiquitin-Mediated Depletion of Nonactivated R-Smads

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Highlights? Inhibition of TGFβ/BMP signaling by degradation of nonactivated R-Smads ? Total R-Smad pools are regulated through the ubiquitin-proteasome pathway ? Ubiquitin proteases USP9x and USP34 interact directly with R-Smads ? Indirubin derivative E738 controls BMP/TGFβ signaling though R-Smad depletion     

Insights into a Divergent Phenazine Biosynthetic Pathway Governed by a Plasmid-Born Esmeraldin Gene Cluster

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Highlights? Esm gene cluster resides on a highly unstable giant plasmid ? EsmA1 and A2 work together to promote the formation of phenazine-1,6-dicarboxylic acid ? Polyketide synthase enzymes EsmB1–B5 catalyze the unique methyl transfer ? Atypical polyketide synthase enzymes EsmD1–D3 catalyze the esterification.     

A Synthetic Substrate of DNA Polymerase Deviating from the Bases,Sugar, and Leaving Group of Canonical Deoxynucleoside Triphosphates

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Highlights? A highly modified nucleotide as substrate for polymerases ? The reversibility of the polymerase reaction at the template level ? Synthesis of a nucleoside with two anomeric centers     

Identification of exosite-targeting inhibitors of anthrax lethal factor by high-throughput screening

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Highlights? Development of an assay for LF protease using a full-length protein substrate ? Lichen depsidones identified as exosite-targeting LF inhibitors ? Exosite inhibitors protect macrophages from LF cytotoxicity     

Fluorescence Imaging of Single-Copy DNA Sequences within the Human Genome Using PNA-Directed Padlock Probe Assembly

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Highlights? PNA-directed assembly of the labeling complex on duplex DNA ? Padlock probes combined with rolling circle amplification for signal amplification ? Multitarget visualization within the human genome with high sequence selectivity     

Reconstitution of Nucleosome Demethylation and Catalytic Properties of a Jumonji Histone Demethylase

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Highlights? Catalytic domain of JMJD2A (cJMJD2A) removes methyl marks in a distributive manner ? Homogeneously methylated nucleosomes were used as substrates ? Quantitative assay for nucleosome demethylation has been developed     

Development of Antibiotic Activity Profile Screening for the Classification and Discovery of Natural Product Antibiotics

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Highlights? Antibiotics can be classified by structural class based on biological fingerprints ? BioMAP predicts the presence of known compounds in natural product extracts ? BioMAP reveals compounds with unique antibacterial properties ? A naphthoquinone antibiotic with a unique carbon skeleton has been discovered     

A Yeast Chemical Genetic Screen Identifies Inhibitors of Human Telomerase

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Highlights? Growth arrest induced by human telomerase in yeast is chemically reversible ? Readout is sensitive to telomerase catalytic activity and telomere recruitment ? Three cell-permeable compounds also inhibit purified human telomerase ? Yeast can be successfully used to screen for human telomerase inhibitors     

A LOV2 Domain-Based Optogenetic Tool to Control Protein Degradation and Cellular Function

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Highlights? Optogenetic tool to control the stability of soluble and membrane proteins ? Engineered using the LOV2 domain and a murine ornithine decarboxylase-like degron ? Creation of light-switchable, conditional mutants ? Graded response to very low blue light intensities allows yeast photography     

Identification of JadG as the B Ring Opening Oxygenase Catalyzing the Oxidative C-C Bond Cleavage Reaction in Jadomycin Biosynthesis

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Highlights? JadG catalyzes the oxidative C-C bond B ring cleavage of dehydrorabelomycin ? JadG needs FMNH₂ or FADH₂ as cofactors ? JadY is a flavin reductase that could supply FMNH₂ or FADH₂ for JadG     

Picoliter cell lysate assays in microfluidic droplet compartments for directed enzyme evolution

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Highlights? Microfluidic droplet compartments miniaturize cell lysate screening assays ? Picoliter single-cell lysate assays comparable in sensitivity to macroscale ? Directed evolution results in improved clones validating this experimental set-up ? Precision of droplet sorting enables enrichment of clones with slight improvements     

Structural and functional investigation of the intermolecular interaction between NRPS adenylation and carrier protein domains

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Highlights? Crystallographic structure of NRPS adenylation and PCP domain interface ? NRPS adenylation C-terminal domain rotation creates appropriate PCP interface ? Mechanism-based inhibitor traps conformationally flexible proteins ? Structure-guided mutagenesis improves noncognate NRPS interactions     

Interplay between the Ribosomal Tunnel,Nascent Chain,and Macrolides Influences Drug Inhibition

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Highlights? Macrolides exhibit nascent polypeptide chain–dependent inhibition ? Peptides can form specific interactions with the ribosomal tunnel ? A covalent bond between tylosin and the ribosome is necessary for inhibitory activity     

Morphobase,an Encyclopedic Cell Morphology Database,and Its Use for Drug Target Identification

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Highlights? Development of an encyclopedia of cell morphology, Morphobase ? Small molecules classified by mode of action with Morphobase ? Morphobase system rapidly predicts molecular targets of compounds ? NPD6689 targets tubulin and is a lead for a class of antitubulin drugs     

Terpendole E,a Kinesin Eg5 Inhibitor,Is a Key Biosynthetic Intermediate of Indole-Diterpenes in the Producing Fungus Chaunopycnis alba

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Highlights? The terpendole biosynthetic gene cluster was isolated ? Terpendole E is a key biosynthetic intermediate of indole-diterpenes ? Terpendole E was overproduced by gene knockout of the bispecific enzyme TerP ? Indole-diterpene biosynthetic pathways can be classified into two groups     

Discovery of Peptoid Ligands for Anti-Aquaporin 4 Antibodies

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Highlights? Peptoid ligands for anti-AQP4 autoantibodies that drive NMO have been identified ? Some of these peptoids provide an accurate blood test for the disease