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Caltractin (centrin) is a member of the calmodulin subfamily of EF-hand

3,4-dihydro-2H-1,2,4,3-triazaborol-3-yl-lithium 3 was synthesized and fully characterized. The (11)B NMR spectrum, X-ray diffraction analysis, and computational studies revealed the ionic nature of the B-Li bond, and indeed 3 displays nucleophilic property which allowed preparation of a series of 1,2,4,3-triazaborol-3-yl-metal complexes (Al; 5, Au; 6, Zn; 7, Mg; 8, Sb; 9, and Bi; 10). 3 reacted with CO (1 atm) and various isonitriles under ambient condition, and mechanistic study suggests that the reactions with CO and aryl isonitriles proceed via an insertion of CO and isonitrile carbon into the B-Li bond followed by isomerization to yield transient carbene species, one of which was confirmed by trapping with S8. With PhNC, compounds 5 and 7·(thf) underwent exchange of THF molecule coordinating to the metal center with isonitrile, whereas insertion of isonitrile carbon occurred at the B-Bi bond in 10 which afforded stable bismuth (boryl)iminomethane 20.

To evaluate its potential as a ligand discovery tool, we compare a newly developed 1D protein-observed fluorine NMR (PrOF NMR) screening method with the well-characterized ligand-observed H CPMG NMR screen. We selected the first bromodomain of Brd4 as a model system to benchmark PrOF NMR because of the high ligandability of Brd4 and the need for small molecule inhibitors of related epigenetic regulatory proteins. We compare the two methods' hit sensitivity, triaging ability, experiment speed, material consumption, and the potential for false positives and negatives. To this end, we screened 930 fragment molecules against Brd4 in mixtures of five and followed up these studies with mixture deconvolution and affinity characterization of the top hits. In selected examples, we also compare the environmental responsiveness of theF chemical shift to H in 1D-protein observedH NMR experiments. To address concerns of perturbations from fluorine incorporation, ligand binding trends and affinities were verified via thermal shift assays and isothermal titration calorimetry. We conclude that for the protein understudy here, PrOF NMR and H CPMG have similar sensitivity, with both being effective tools for ligand discovery. In cases where an unlabeled protein can be used, 1D protein-observedH NMR may also be effective; however, the F chemical shift remains significantly more responsive.

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Increasing the success rate and throughput of drug discovery will require efficiency improvements throughout the process that is currently used in the pharmaceutical community, including the crucial step of identifying hit compounds to act as drivers for subsequent optimization. Hit identification can be carried out through large compound collection screening and often involves the generation and testing of many hypotheses based on available knowledge. In practice, hypothesis generation can involve the selection of promising chemical structures from compound collections using predictive models built from previous screening/ assay results. Available physical collections, typically used during hit identification, are of the order of 10 6 compounds but represent only a small fraction of the small molecule drug-like chemical space. In an effort to survey a larger portion of chemical space and eliminate inefficiencies during hit identification, we introduce a new process, termed Idea2Data (I2D) that tightly integrates computational and experimental components of the drug discovery process. I2D provides the ability to connect a vast virtual collection of compounds readily synthesizable on automated synthesis systems with computational predictive models for the identification of promising structures. This new paradigm enables researchers to process billions of virtual molecules and select structures that can be prepared on automated systems and made available for biological testing, allowing for timely hypothesis testing and follow-up. Since its introduction, I2D has positively impacted several portfolio efforts through identification of new chemical scaffolds and functionalization of existing scaffolds. In this Innovations paper, we describe the I2D process and present an application for the discovery of new ULK inhibitors.